Compounds

ABSTRACT

The invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions or disorders which are mediated via the GPR38 receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/768,339, filed Jun. 26, 2007 and claims priority of GB ApplicationNos. 0612844.1, filed Jun. 29, 2006 and 0711525.6, filed Jun. 14, 2007,the disclosures of which are incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel benzylpiperazine derivativeshaving pharmacological activity, processes for their preparation,pharmaceutical compositions containing them and their use in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

GPR38 is a 7-transmembrane, G-protein coupled receptor, with highaffinity for the peptide motilin [Feighner et al., Science 1999, 284,2184], suggesting that endogenous motilin exerts all or most of itsactivity via this receptor.

Motilin is a 22 amino acid peptide found in large amounts withinendocrine-like cells of the gastrointestinal tract, and especially inthe duodenum-jejunum areas. During fasting, the peptide is known to beassociated with the onset of Phase III migrating complex activity withinthe stomach [Boivin et al., Dig. Dis. Sci. 1992, 37, 1562], suggesting arole in the mechanisms of prokinetic activity. Motilin is also releasedfrom the gut during feeding, sham feeding, gastric distension or by oralor intravenous nutrient application [Christofides et al., Gut 1979, 20,102; Bormans et al., Scand. J. Gastroenterol. 1987, 22, 781], suggestingadditional roles for this peptide in the modulation of motility patternsduring feeding.

In animals or in man, motilin has long been known to increasegastrointestinal motility, and promote gastric emptying and intestinalpropulsion in an anal direction, during both fasting and fed conditions.This activity is thought to be primarily due to a facilitation of atleast the cholinergic excitatory function of the gut [Van Assche et al.,Eur. J. Pharmacol. 1997, 337, 267], perhaps also involving theactivation of the vagus nerve [Mathis & Malbert, Am. J. Physiol. 1998,274, G80]. In addition, higher concentrations of motilin directly evokea small contraction of the muscle [Van Assche et al., Eur. J. Pharmacol.1997, 337, 267].

The antibiotic erythromycin was shown to mimic the gastrointestinalactivity of motilin, in addition to its previously-described antibioticproperties [see Peeters, in Problems of the Gastrointestinal Tract inAnaesthesia Ed., Herbert M K et al. Springer-Verlag, Berlin, Heidelberg1999, pp 39-51]. More recently, erythromycin has been shown to activatethe GPR38 receptor, confirming its ability to mimic the function ofmotilin [Carreras et al., Analyt. Biochem. 2002, 300, 146]. In addition,the availability of this non-peptide motilin receptor agonist hasallowed at least some clinical studies to be undertaken in order toexamine the clinical potential of motilin receptor agonists. Thesestudies have consistently demonstrated an ability to increase gastricemptying in various conditions associated with gastroparesis, such asfunctional dyspepsia and diabetic gastroparesis. Further, erythromycinhas been shown to increase lower esophageal sphincter pressure in man,which together with the increase in gastric emptying, suggests a role inthe treatment of gastroesophageal reflux disorders (GERD). Finally,erythromycin has been used to promote intestinal propulsive activity,finding clinical utility in the treatment of pseudo-obstruction and inconditions with impaired colonic motility [Peeters, in Problems of theGastrointestinal Tract in Anaesthesia Ed., Herbert M K et al.Springer-Verlag, Berlin, Heidelberg 1999, pp 39-51].

Consequently it is expected that agonists at the GPR38 receptor willmimic the activity of motilin or of other substances acting at thisreceptor, such as erythromycin, and find clinical utility in thetreatment of gastrointestinal disorders associated with hypomotility,especially the functional bowel disorders such as GERD, functionaldyspepsia (FD) and irritable bowel syndrome (IBS). The compounds willalso be useful for the treatment of other GI conditions where the causeis known and in which GI motility is reduced. Such conditions includeconstipation, caused by various diseases such as those associated withneuropathy, and/or by the administration of other drugs, intestinalpseudo-obstruction, paralytic ileus following surgery or some othermanipulation, gastric stasis or hypomotility caused by various diseasessuch as diabetes and/or by the administration of other drugs, or inenterally fed patients. Interestingly, the ability of motilin orerythromycin to activate the vagus nerve, the association of this nervewith changes in feeding behaviour [e.g. Furness et al., Auton. Neurosci.2001, 92, 28] and the chromosomal location of GPR38 [based on Ensembl:13q21.1 (58.46-59.46 Mb)] within the markers (D13S257-13q14.11 toD13S258 at 13q21.33) of a locus associated with obesity [Feitosa et al,Am. J. Hum. Genet. 2002, 70, 72] also suggests that agonists active atthe GPR38 receptor will, in addition to promoting gastrointestinalmotility, facilitate eating behaviours in at least those patients inwhich some degree of appetite suppression or cachexia is present. Suchactivity indicates that agonists at this receptor will find clinicalutility in the treatment of symptoms associated with—for example—thetreatment of cancer or by the presence of the cancer itself.

In addition to the ability of motilin receptor agonists to promotegastrointestinal motility, the association of motilin gene polymorphismwith Crohn's disease [Annese et al., Dig. Dis. Sci. 1998, 43, 715-710]and the changes in motilin receptor density during colitis [Depoortereet al., Neurogastroenterol. Motil. 2001, 13, 55] suggests a utility foragonists at the motilin receptor for the treatment of inflammatory bowelconditions in general.

Finally, GPR38 is also found in regions outside the gastrointestinaltract. These areas include the pituitary, adipose tissue, urinarybladder and certain areas of the brain. The former suggests clinicalutility in the promotion of pituitary function, such as the release ofgrowth hormone secretagogues, the presence within adipose tissue againsuggests a role in the control of body weight, and the presence withinthe urinary bladder suggests a role for agonists at this receptor in thetreatment of incontinence. The presence of GPR38 within the brainsupports the gastrointestinal and feeding utilities already mentioned,but in addition, suggests an involvement of the receptor in a greaterspectrum of vagal-hypothalamic functions.

WO9410185, EP838469, WO9823629, DE19805822, and U.S. Pat. No. 6,165,985claim erythromycin derivatives targeting GPR38 for use in disordersrelating to gastrointestinal motility. WO9921846, WO0185694, WO0168620,WO0168621, and WO0168622 disclose a series of small molecule antagonistsof the GPR38 receptor. JP07138284 and EP807639 disclose peptideagonists. JP09249620, WO02092592, WO05027637, US2005065156 and Li etal., (2004, Journal of Medicinal Chemistry, 47(7) p1704-1708) discloseseries of small molecule agonists. WO 05012331 and WO 05012332 fromTranzyme disclose macrocyclic compounds which are agonists orantagonists of mammalian motilin or ghrelin receptors. WO 06127252 fromKosan discloses erythromycin derivatives.

WO07/007,018 describes compounds of formula (A), which have activity asagonists of the GPR38 receptor

WO07/012,479 describes compounds of formula (B), which have activity asagonists of the GPR38 receptor

A structurally novel class of compounds has now been found whichprovides agonists of the GPR38 receptor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention therefore provides compounds of formula (I) andsalts thereof (hereinafter known as “compounds of the invention”):

whereinA is phenyl or a 6-membered heteroaryl ring, optionally substituted withone substituent selected from halogen, C₍₁₋₄₎alkyl and C₍₁₋₄₎alkoxy;R¹ and R² are independently H or C₍₁₋₄₎alkyl;R³ is an optionally substituted phenyl, heteroaryl ring, or heterocyclicring;B is an optionally substituted phenyl, 6-membered heteroaryl ring or6-membered heterocyclic ring connected to the amide carbon via a carbonatom;Y is a bond, NH, N—C₍₁₋₄₎alkyl, O, C═O, or CH₂;R⁴ is hydrogen, C₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxyalkyl.

The present invention also provides compounds of formula (IA) or apharmaceutically acceptable salt or solvate thereof:

whereinA is phenyl or a 6-membered heteroaryl ring, optionally substituted withhalogen, C₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxy;R¹ and R² are independently H or C₍₁₋₄₎ alkyl;R³ is an optionally substituted phenyl, heteroaryl ring, or heterocyclicring;B is an optionally substituted phenyl, a 6-membered heteroaryl ring or a6-membered heterocyclic ring connected to the amide carbon via a carbonatom;Y is a bond, NH, N—C₍₁₋₄₎alkyl, O, C═O, or CH₂;R⁴ is hydrogen or C₍₁₋₄₎ alkyl.

When R³ or B is substituted, it may have 1, 2 or 3 substituents, eachindependently selected from halogen, C₍₁₋₄₎alkyl, C₍₁₋₄₎alkoxy,C₍₃₋₇₎cycloalkyl, hydroxy, trifluoromethoxy, trifluoromethyl, nitro,cyano, phenyl, NH₂, NHR⁵, NR⁵R⁵, NHCOR⁵, NHSO₂R⁵, C(O)CF₃,C(O)C₍₁₋₄₎alkyl, C(O)C₍₃₋₇₎cycloalkyl, C(O)OC₍₁₋₄₎alkyl,C(O)OC₍₍₃₋₇₎cycloalkyl, OC(O)C₍₁₋₄₎alkyl, OC(O)C₍₃₋₇₎cycloalkyl, CONH₂,CONHR⁵, CONR⁵R⁶, SOR⁶, SO₂CF₃, SO₂R⁶, OSO₂R⁶, OSO₂CF₃, SO₂NH₂, SO₂NHR⁵,SO₂NR⁵R⁶, where R⁵ and R⁶ may be the same or different and representC₍₁₋₄₎ alkyl, phenyl optionally substituted with halogen or 5 or 6membered heteroaryl optionally substituted with halogen.

In one embodiment R³ is substituted by fluorine, chlorine, cyano, CONH₂,methyl, methoxy or trifluoromethoxy.

In one embodiment B is substituted by methyl.

The term “alkyl” as a group or part of a group e.g. alkoxy orhydroxyalkyl refers to a straight or branched alkyl group in allisomeric forms. The term “C₍₁₋₄₎ alkyl” refers to an alkyl group, asdefined above, containing at least 1, and at most 4 carbon atomsExamples of such alkyl groups include methyl, ethyl, propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, or tert-butyl, Examples of such alkoxygroups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy,iso-butoxy, sec-butoxy and tert-butoxy.

Suitable C₍₃₋₇₎cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, cycloheptyl.

As used herein, the term “halogen” refers to fluorine (F), chlorine(Cl), bromine (Br), or iodine (I) and the term “halo” refers to thehalogen: fluoro (—F), chloro (—Cl), bromo (—Br) and iodo (—I).

The term “heteroaryl ring” represents a 5 or 6 membered unsaturatedaromatic ring which comprises one or more heteroatoms. When the termheteroaryl represents a 5 membered group it contains a heteroatomselected from O, N or S and may optionally contain a further 1 to 3nitrogen atoms. When heteroaryl represents a 6-membered group itcontains from 1 to 3 nitrogen atoms. Examples of such 5 or 6 memberedheteroaryl rings include pyrrolyl, triazolyl, thiadiazolyl, tetrazolyl,imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, furazanyl, furanyl, thienyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl and triazinyl.

The term “heterocyclic ring” represents a saturated or partiallysaturated 5 or 6 membered ring which comprises one or more heteroatomsselected from nitrogen, oxygen and sulphur. Examples of suchheterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl.

In one embodiment of the invention A is optionally substituted phenyl orpyridyl.

In one embodiment of the invention R¹ is hydrogen or methyl.

In one embodiment of the invention R² is hydrogen or methyl.

In one embodiment of the invention R³ is optionally substituted phenyl,morpholinyl, piperidinyl, oxadiazolyl, pyridyl, pyrimidinyl, imidazolyl,pyrrolyl. In a further embodiment R³ is optionally substituted phenyl,morpholinyl or piperidinyl.

In one embodiment of the invention B is optionally substituted phenyl,piperidinyl, pyrimidinyl or pyridyl.

In one embodiment of the invention Y is NH, O, CH₂, C═O or a bond.

In one embodiment of the invention R⁴ is hydrogen, methyl, ethyl,methoxyethyl or isopropyl. In a further embodiment R⁴ is methyl.

In one embodiment of the invention,

A is optionally substituted phenyl or pyridyl; and/orR¹ is hydrogen or methyl; and/orR² is hydrogen or methyl; and/orR³ is optionally substituted phenyl, morpholinyl or piperidinyl; and/orB is optionally substituted phenyl, piperidinyl, pyrimidinyl or pyridyl;and/orY is NH, O, CH₂, C═O or a bond; and/orR⁴ is methyl; and salts thereof.

In another embodiment of the invention,

A is optionally substituted phenyl or pyridyl; and/orR¹ is hydrogen or methyl; and/orR² is hydrogen or methyl; and/orR³ is optionally substituted phenyl, morpholinyl, piperidinyl,oxadiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrrolyl; and/orB is optionally substituted phenyl, piperidinyl, pyrimidinyl or pyridyl;and/orY is NH, O, CH₂, C═O or a bond; and/orR⁴ is hydrogen, methyl, ethyl, methoxyethyl or isopropyl; and saltsthereof.

It is to be understood that the present invention covers allcombinations of the substituent groups described hereinabove.

In a further embodiment of the invention the (piperazinyl)methylenegroup and [—N(R⁴)—C(═O)—B—Y—R³] group are para- to each other acrossring A and, where B represents optionally substituted phenyl or pyridyl,the [(piperazinyl)methylene-A-N(R⁴)—C(═O)-] group and [—Y—R³] group areeither para- or meta- to each other across ring B.

In certain of the compounds of formula (I), dependent upon the nature ofthe substituent there are chiral carbon atoms, such as the carbon atommarked with an “*”, and therefore compounds of formula (I) may exist asstereoisomers. The invention extends to all optical isomers such asstereoisomeric forms of the compounds of formula (I) includingenantiomers, diastereoisomers and mixtures thereof, such as racemates.The different stereoisomeric forms may be separated or resolved one fromthe other by conventional methods or any given isomer may be obtained byconventional stereoselective or asymmetric syntheses. Preferredcompounds of formula (I) wherein R¹ and R² are both methyl are thosewherein the piperazine C* carbons have the 3R,5S-configuration.Preferred compounds of formula (I) wherein one of R¹ and R² is methyland the other is hydrogen are those wherein the piperazine C* carbon hasthe S-configuration

Certain of the compounds herein can exist in various tautomeric formsand it is to be understood that the invention encompasses all suchtautomeric forms.

Suitable compounds of the invention are:

-   6-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E1)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E2)-   1-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E3)-   6-(4-fluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E4)-   6-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E5)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(4-morpholinyl)-3-pyridinecarboxamide    (E6)-   4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-biphenylcarboxamide    (E7)-   6-(4-fluorophenyl)-2-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E8)-   1-[(3-fluorophenyl)carbonyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E9)-   1-[(3-fluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E10)-   1-(4-chlorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E11)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(1-piperidinyl)-3-pyridinecarboxamide    (E12)-   6-(2-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E13)-   6-(2,4-difluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E14)-   6-(3,4-difluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E15)-   6-(3-fluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E16)-   4-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E17)-   6-(3-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E18)-   6-(4-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E19)-   4-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E20)-   N-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-6-(4-fluorophenyl)-N,2-dimethyl-3-pyridinecarboxamide    (E21)-   2-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E22)-   N-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-6-(4-fluorophenyl)-N-methyl-3-pyridinecarboxamide    (E23)-   4-[(2-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E24)-   3-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E25)-   3-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E26)-   6-[(4-fluorophenyl)amino]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E27)-   2-(4-fluorophenyl)-N,4-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-5-pyrimidinecarboxamide    (E28)-   2-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-5-pyrimidinecarboxamide    (E29)-   6-(4-fluorophenyl)-N,2-dimethyl-N-(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E30)-   6-(4-fluorophenyl)-N-methyl-N-(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E31)-   4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-biphenylcarboxamide    (E32)-   4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-biphenylcarboxamide    (E33)-   6-(3-fluorophenyl)-N-methyl-N-[4-(1-piperazinylmethyl)phenyl]-3-pyridinecarboxamide    (E34)-   6-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E35)-   6-[(2-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E36)-   6-(3-fluorophenyl)-N,2-dimethyl-N-[4-(1-piperazinylmethyl)phenyl]-3-pyridinecarboxamide    (E37)-   6-(2-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E38)-   6-[2-(aminocarbonyl)phenyl]-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E39)-   6-(2-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E40)-   6-(3-fluorophenyl)-N-methyl-N-(3-methyl-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E41)-   6-(3-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E42)-   6-[(3-cyanophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E43)-   N-(2-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-fluorophenyl)-N-methyl-3-pyridinecarboxamide    (E44)-   5-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E45)-   5-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E46)-   N-(2-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide    (E47)-   5-[(3-cyanophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E48)-   5-[(4-fluorophenyl)amino]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E49)-   1-[(3,4-difluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E50)-   1-[(4-fluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E51)-   N-(3-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-fluorophenyl)-N-methyl-3-pyridinecarboxamide    (E52)-   N-(3-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide    (E53)-   1-[(3-cyanophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E54)-   1-[(4-cyanophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide    (E55)-   6-(3-fluorophenyl)-N-(1-methylethyl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E56)-   N-ethyl-6-(3-fluorophenyl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E57)-   6-(3-fluorophenyl)-N-[2-(methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E58)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(3-methyl-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E59)-   6-(3-fluorophenyl)-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide    (E60)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide    (E61)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E62)-   6-(4-fluoro-1-piperidinyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E63)-   6-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E64)-   N-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E65)-   N-ethyl-6-[(4-fluorophenyl)oxy]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E66)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-pyridinyloxy)-3-pyridinecarboxamide    (E67)-   6-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E68)-   6-(4,4-difluoro-1-piperidinyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E69)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(6-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-pyridinyl)-3-pyridinecarboxamide    (E70)-   5-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E71)-   5-(3-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E72)-   N-methyl-5-[3-(methyloxy)phenyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E73)-   N-methyl-5-[4-(methyloxy)phenyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E74)-   5-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E75)-   6-(4-fluorophenyl)-N-methyl-N-(6-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-pyridinyl)-3-pyridinecarboxamide    (E76)-   6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-methyl-5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide    (E77)-   N,2′-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3,4′-bipyridine-6-carboxamide    (E78)-   6-[(4-fluorophenyl)oxy]-N-[2-(methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide    (E79).-   N-(3-chloro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide    (E80)-   N,2′-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2,4′-bipyridine-5-carboxamide    (E81)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(2-pyridinyl)benzamide    (E82)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(2-pyrimidinyl)benzamide    (E83)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(1H-pyrazol-1-yl)benzamide    (E84)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(1H-pyrrol-1-yl)-3-pyridinecarboxamide    (E85)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-{[4-(trifluoromethyl)phenyl]carbonyl}benzamide    (E86)-   5-(4-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E87)-   6-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide    (E88)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(6-methyl-3-pyridinyl)benzamide    (E89)-   N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(2-pyrazinyl)benzamide    (E90)-   6-(4-fluorophenyl)-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-2-pyridinecarboxamide    (E91)-   6-(3-fluorophenyl)-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-2-pyridinecarboxamide    (E92)-   2-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide    (E93)    and salts thereof.

One embodiment of the invention is6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamideor a salt thereof.

A further embodiment of the invention is6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamidefumarate salt.

One embodiment of the invention is6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-methyl-5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamideor a salt thereof.

Included within the scope of the “compounds of the invention” are allsalts, solvates, hydrates, complexes, polymorphs, prodrugs,radiolabelled derivatives, stereoisomers and optical isomers of thecompounds of formula (I).

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

The compounds of formula (I) and salts thereof may be prepared incrystalline or non-crystalline form, and, if crystalline, may optionallybe hydrated or solvated. This invention includes within its scopestoichiometric hydrates or solvates as well as compounds containingvariable amounts of water and/or solvent.

Salts and solvates having non-pharmaceutically acceptable counter-ionsor associated solvents are within the scope of the present invention,for example, for use as intermediates in the preparation of othercompounds of formula (I) and their pharmaceutically acceptable salts.

Additionally, the compounds of formula (I) may be administered asprodrugs. As used herein, a “prodrug” of a compound of formula (I) is afunctional derivative of the compound which, upon administration to apatient, eventually liberates the compound of formula (I) in vivo.Administration of a compound of formula (I) as a prodrug may enable theskilled artisan to do one or more of the following: (a) modify the onsetof the compound in vivo; (b) modify the duration of action of thecompound in vivo; (c) modify the transportation or distribution of thecompound in vivo; (d) modify the solubility of the compound in vivo; and(e) overcome or overcome a side effect or other difficulty encounteredwith the compound. Typical functional derivatives used to prepareprodrugs include modifications of the compound that are chemically orenzymatically cleaved in vivo. Such modifications, which include thepreparation of phosphates, amides, esters, thioesters, carbonates, andcarbamates, are well known to those skilled in the art.

The invention also includes isotopically-labeled compounds, which areidentical to those described herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, and chlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F,¹²³I and ¹²⁵I. Compounds of the invention that contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of the present invention. Isotopically-labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H, ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. ¹¹C and ⁸F isotopes are particularly useful in PET(positron emission tomography), and ¹²⁵I isotopes are particularlyuseful in SPECT (single photon emission computerized tomography), alluseful in brain imaging. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds of theinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, then substitutinga readily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

In a further aspect, this invention provides a process for thepreparation of a compound of formula (I)

as defined above or a salt thereof, which process comprises reacting ofa compound of formula (II)

wherein R¹, R², A and R⁴ are as defined above and Q is hydrogen or asuitable nitrogen protecting group such as tert-butyloxycarbonyl (Boc)or benzyloxycarbonyl (Cbz), and a compound of formula R³—Y—B—C(═O)-L¹wherein R³, B and Y are as defined above and L¹ is a leaving group suchas halogen, alkanoyloxy or sulfonyloxy, using conditions suitable forthe formation of an amide bond. For example, where L¹ representshalogen, the reaction may be carried out using a suitable base such astriethylamine in an inert solvent such as dichloromethane.

And thereafter optionally carrying out one or more of the followingreactions:

-   -   a) Converting one compound of formula (I) into another compound        of formula (I);    -   b) Removing any protecting group;    -   c) Forming a suitable pharmaceutically acceptable salt or        solvate of the compound so formed.

Alternatively, a compound of formula (I) as defined above or a saltthereof, may be prepared by a process which comprises reacting acompound of formula (II) as defined above with a compound of formulaR³—Y—B—C(═O)—OH where R³, B and Y are defined above in the presence of asuitable coupling reagent such as N,N′-dicyclohexylcarbodiimide (DCC),N-benzyl-N′-cyclohexylcarbodiimide resin or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC); optionally in thepresence of 1-hydroxybenzotriazole (HOBt); in a suitable solvent such asdichloromethane, dimethylformamide or mixtures thereof.

And thereafter optionally carrying out one or more of the followingreactions:

-   -   a) Converting one compound of formula (I) into another compound        of formula (I);    -   b) Removing any protecting group;    -   c) Forming a suitable pharmaceutically acceptable salt or        solvate of the compound so formed.

Compounds of formula (II) where A represents a 1,4-phenylene group maybe prepared by reaction of a compound of formula (III)

wherein R¹ and R² are as defined above, R⁷ represents optionalsubstitution in the phenylene moiety as defined for A above and Q ishydrogen or a suitable nitrogen protecting group such astert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz) with anappropriate aldehyde, ketone or enol ether to provide R⁴, usingconditions suitable for a reductive amination; for example in thepresence of a suitable reducing agent such as sodium borohydride and ina suitable solvent such as methanol and optionally in the presence of asuitable base such as sodium methoxide.

Compounds of formula (III) may be prepared by reaction of a compound offormula (IV)

wherein R¹, R², R⁷ and Q are as defined above, using conditions suitablefor a reduction; for example when Q is Boc, hydrogenation in thepresence of a suitable catalyst such as palladium on charcoal orplatinum on charcoal, in a suitable solvent such as methanol andoptionally in the presence of a suitable base such as potassiumhydroxide or triethylamine. Alternatively when Q is Boc or Cbz, thereduction may be carried out using a suitable metal reducing agent suchas iron powder, in the presence of a suitable proton source such asammonium chloride and in a suitable solvent such as aqueous methanol.

Compounds of formula (IV) may be prepared by reaction of a compound offormula (V)

wherein R⁷ is as defined above, with a compound of formula (VI)

wherein R¹, R² and Q are as defined above, using reaction conditionssuitable for a reductive amination, for example in the presence of areducing agent such as sodium tri(acetoxy)borohydride in a suitablesolvent such as dichloromethane or 1,2-dichloroethane.

Alternatively compounds of formula (IV) may be prepared by reaction of acompound of formula (VII)

wherein R⁷ is as defined above and L² represents a leaving group such ashalogen, alkylsulfonyloxy or arylsulfonyloxy, with a compound of formula(VI) as defined above, using conditions suitable for an alkylationreaction, for example use of an appropriate solvent such asN,N-dimethylformamide and a suitable base such as Hunig's base.

Compounds of formula (VII) are commercially available or may be preparedby methods similar to those described in the literature (see for exampleWO 03/053972, WO 03/037898.

Compounds of formula R³—Y—B—C(═O)-L¹ as defined above may be preparedfrom compounds of formula R³—Y—B—C(═O)—OH by reaction with anappropriate reagent for introduction of the leaving group, for examplewhere L¹ is chlorine, treatment with thionyl chloride, or oxalylchloride in the presence of catalytic N,N-dimethylformamide.

An alternative process for preparation of compounds of formula (I)comprises reaction of a compound of formula (VIII)

Wherein R¹, R², R⁴, A, B and Q are as defined above and L³ represents aleaving group such as halogen or trifluoromethylsulfonyloxy, and acompound of formula M¹-Y—R³ wherein R³ and Y are as defined above and M¹represents hydrogen, a metal residue (e.g. alkali metal salt,trialkylstannyl) or a boronic acid, optionally in the presence of asuitable base such as potassium carbonate, cesium carbonate, sodiumcarbonate, sodium hydride or triethylamine and optionally using asuitable transition metal catalyst system such as palladiumacetate/BINAP, copper (I) chloride/2,2,6,6-tetramethyl-3,5-heptanedioneor tetrakis(triphenylphosphine) palladium (0).

And thereafter optionally carrying out one or more of the followingreactions:

-   -   a) Converting one compound of formula (I) into another compound        of formula (I);    -   b) Removing any protecting group;    -   c) Forming a suitable pharmaceutically acceptable salt or        solvate of the compound so formed.

Compounds of formula (VIII) may be prepared by reaction of compounds offormula (II) as defined above with a compound of formula L³-B—C(═O)-L¹or L³-B—C(═O)—OH wherein L¹, L³ and B are as defined above, usingmethods similar and/or analogous to those described above.

An alternative process for preparation of compounds of formula (III)comprises reaction of a compound of formula (VI) as defined above with acompound of formula (IX):

wherein R⁷ is as defined above and Q¹ is a suitable protecting groupsuch as acetyl under conditions suitable for reductive amination asdescribed above, followed by a suitable deprotection step to remove Q¹.

Compounds of formula (IX) are commercially available or may be preparedfrom the corresponding carboxylic acid, using general methods for theconversion of a carboxylic acid to an aldehyde. See, for example, M. B.Smith & J. March, Advanced Organic Chemisty, 5th Edition, J Wiley &Sons, 2001, Chapter 19, p. 1506-1604.

An alternative process for preparation of compounds of formula (II)wherein A represents an optionally substituted 1,4-phenylene group, anoptionally substituted 2,5-pyridyl group or an optionally substituted3,6-pyridyl group comprises reaction of a compound of formula (VI) asdefined above with a compound of formula (X):

wherein A and R⁴ are as defined above, under conditions suitable forreductive amination as described above.

Compounds of formula (X) wherein A represents an optionally substituted1,4-phenylene group or an optionally substituted 2,5-pyridyl group, andR⁴ is as defined above may be prepared by reaction of a compound offormula (XI):

wherein A represents an optionally substituted 1,4-phenylene group or anoptionally substituted 2,5-pyridyl group and L³ is as defined above witha compound of formula R⁴NHQ¹, wherein R⁴ is as defined above and Q¹ is asuitable nitrogen protecting group such as tert-butyloxycarbonyl (Boc),in the presence of a suitable transition metal catalyst system such astris(dibenzylideneacetone) dipalladium(0)/xantphos, in the presence of asuitable base such as cesium carbonate and in a suitable solvent such asdioxane; followed by a suitable deprotection step.

Compounds of formula (XI) wherein A represents an optionally substituted1,4-phenylene group or an optionally substituted 2,5-pyridyl group arecommercially available or may be prepared by reaction of a compound offormula (XII):

wherein A represents an optionally substituted 1,4-phenylene group or anoptionally substituted 2,5-pyridyl group and L³ is as defined above witha suitable reducing agent such as diisobutylaluminium hydride in asuitable solvent such as toluene. Compounds of formula (X) wherein Arepresents an optionally substituted 3,6-pyridyl group may be preparedby reaction of a compound of formula (XIII):

wherein R⁴ is as defined above and R⁷ represents optional substitutionin the pyridine moiety with a suitable reducing agent such asdiisobutylaluminium hydride in a suitable solvent such as toluene.

Compounds of formula (XIII) wherein R⁴ is as defined above and R⁷represents optional substitution of the pyridine moiety with C₍₁₋₄₎alkylor C₍₁₋₄₎alkoxy may be prepared by reaction of a compound of formula(XIV):

wherein R⁷ represents optional substitution of the pyridine moiety withC₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxy and L³ is as defined above with a compoundof formula R⁴NH₂ in a suitable solvent such as THF and optionally in thepresence of a suitable base.

An alternative process for preparation of compounds of formula (III)wherein A represents an optionally substituted 3,6-pyridyl groupcomprises reaction of a compound of formula (VI) as defined above with acompound of formula (XV):

wherein R⁷ represents optional substitution of the pyridine moiety withC₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxy, under conditions suitable for reductiveamination as described above.

Compounds of formula (XV) may be prepared by reaction of a compound offormula (XVI):

wherein R⁷ represents optional substitution of the pyridine moiety withC₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxy and Q¹ is a suitable protecting group suchas trifluoroacetyl, with a suitable reducing agent such asnickel/aluminium alloy in the presence of formic acid and in a suitablesolvent such water.

Compounds of formula (XVI) may be prepared by reaction of a compound offormula (XVII):

wherein R⁷ represents optional substitution of the pyridine moiety withC₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxy, with copper (I) cyanide in a suitablesolvent such as DMF followed by suitable protection of the amino group.When Q¹ is trifluoroacetyl the protection may be carried out usingtrifluoroacetic anhydride in the presence of a suitable base such as2,6-lutidine and in a suitable solvent such as dichloromethane.

Compounds of formula (V), (VI), (XII), (XIV) and (XVII) are commerciallyavailable, described in the literature or can be prepared by analogousor similar methods.

Compounds of formula R³—Y—B—C(═O)—OH are commercially available,described in the literature or can be prepared by analogous or similarmethods (for example, see WO 2003/068749, WO 2004/072069, WO2005/016928, WO 2003/027061, WO 2005/016915, WO 1997/025309, WO2005/047278, WO 2002/016356, WO 2007/041634 and WO 2005/073210).

Compounds of formula L³-B—C(═O)-L¹ are either commercially available,described in the literature or can be prepared by analogous or similarmethods.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in Greene T. W. & Wuts P. G. M., Protective groups inorganic synthesis, 2^(nd) Edition, New York, Wiley (1991), can be used.For example, primary and secondary amines can be protected asphthalimide, trifluoroacetyl, benzyl, tert-butyloxycarbonyl,benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can beprotected as esters. Aldehyde or ketone groups can be protected asacetals, ketals, thioacetals or thioketals. Deprotection of such groupsis achieved using conventional procedures well known in the art. Forexample, protecting groups such as tert-butyloxycarbonyl may be removedusing an acid such as hydrochloric or trifluoroacetic acid in a suitablesolvent such as dichloromethane, diethyl ether, 1,4-dioxane, isopropanolor mixtures thereof.

Salts may be prepared conventionally by reaction with the appropriateacid or acid derivative.

The present invention also provides compounds of formula (II) and (VIII)as shown above wherein R¹, R², R⁴, A and B are as defined for formula(I), Q is hydrogen or a suitable protecting group such astert-butyloxycarbonyl (BOC) or benzyloxycarbonyl (CBZ) and L³ is aleaving group such as halogen or trifluoromethylsulfonyloxy. Thesecompounds are useful as intermediates in the preparation of compounds ofthe present invention.

The potencies and efficacies of the compounds of this invention forGPR38 can be determined by FLIPR assay performed on the human clonedreceptor as described herein. Compounds of formula (I) have demonstratedpartial or full agonist activity at the GPR38 receptor, using the FLIPR(FLuorometric Imaging Plate Reader) functional assays described herein.

Compounds of formula (I) and pharmaceutically acceptable salts thereofare therefore of use in the treatment of conditions or disorders whichare mediated via the GPR38 receptor. In particular the compounds offormula (I) and pharmaceutically acceptable salts thereof are of use inthe treatment of certain gastrointestinal disorders such asgastroesophageal reflux disorders, functional dyspepsia, irritable bowelsyndrome, constipation, intestinal pseudo-obstruction, paralytic ileusfollowing surgery or other manipulation, emesis, gastric stasis orhypomotility caused by various diseases such as diabetes and/or by theadministration of other drugs, or in enterally fed patients, Crohn'sdisease, colitis, cachexia associated with advanced diseases such ascancer and/or the treatment thereof, and other disorders such asincontinence (herein after referred to as the “Disorders of theInvention”).

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms.

Thus the invention also provides compounds of formula (I) andpharmaceutically acceptable salts thereof for use as a therapeuticsubstance, in particular in the treatment of conditions or disordersmediated via the GPR38 receptor. In particular the invention providescompounds of formula (I) and pharmaceutically acceptable salts thereoffor use as a therapeutic substance in the treatment of gastrointestinaldisorders such as gastroesophageal reflux disorders, functionaldyspepsia, irritable bowel syndrome, constipation, intestinalpseudo-obstruction, paralytic ileus following surgery or othermanipulation, emesis, gastric stasis or hypomotility caused by variousdiseases such as diabetes and/or by the administration of other drugs,or in enterally fed patients, Crohn's disease, colitis, cachexiaassociated with advanced diseases such as cancer and/or the treatmentthereof, and other disorders such as incontinence.

The invention further provides a method of treatment of conditions ordisorders in mammals including humans which can be mediated via theGPR38 receptor, which comprises administering to the sufferer atherapeutically safe and effective amount of a compounds of formula (I)or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides for the use of compounds offormula (I) and pharmaceutically acceptable salts thereof in themanufacture of a medicament for use in the treatment of the conditionsor disorders mediated via the GPR38 receptor.

In order to use the compounds of formula (I) and pharmaceuticallyacceptable salts thereof in therapy, they will normally be formulatedinto a pharmaceutical composition in accordance with standardpharmaceutical practice. The present invention also provides apharmaceutical composition, which comprises a compound of formula (I) ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); tabletting lubricants (e.g. magnesiumstearate, talc or silica); disintegrants (e.g. potato starch or sodiumstarch glycollate); and acceptable wetting agents (e.g. sodium laurylsulphate). The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound or pharmaceutically acceptable salt thereof.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of formula (I) or pharmaceutically acceptable saltthereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of formula (I) or pharmaceutically acceptable saltthereof and a sterile vehicle, optionally with an added preservative.The compositions may take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising and/or dispersing agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may also be formulated in rectal compositions such assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

The compounds of formula (I) or pharmaceutically acceptable salts mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds of formula (I) or pharmaceutically acceptable salts may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, the compounds formula (I) orpharmaceutically acceptable salts thereof may be formulated as solutionsfor administration via a suitable metered or unitary dose device oralternatively as a powder mix with a suitable carrier for administrationusing a suitable delivery device. Thus compounds of formula (I) orpharmaceutically acceptable salts thereof may be formulated for oral,buccal, parenteral, topical (including ophthalmic and nasal), depot orrectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be formulated for topical administration in the form ofointments, creams, gels, lotions, pessaries, aerosols or drops (e.g.eye, ear or nose drops). Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Ointments for administration to theeye may be manufactured in a sterile manner using sterilised components.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 500 mg or 1.0 to 200 mg, and such unit doses may beadministered more than once a day, for example two or three times a day.

Compounds of formula (I) and pharmaceutically acceptable salts thereofmay be used in combination preparations. For example, the compounds offormula (I) and pharmaceutically acceptable salts thereof may be used incombination with one or more compounds with activity in reducing gastricacid; one or more compounds with activity in reducing gastro-esophagealreflux; one or more compounds with activity in reducing esophago-gastricirritancy or inflammation, especially when used to alleviate erosive ornon-erosive esophagitis; one or more compounds with analgesic activity;and/or one or more compounds with mixed activity on motility and pain.

Examples of compounds with activity in reducing gastric acid include H2receptor antagonists, acid pump antagonists and proton pump inhibitors.Examples of compounds with activity in reducing gastro-esophageal refluxinclude agonists at GABA-B. Examples of compounds with analgesicactivity include compounds active at Neurokinin receptors (NK1, 2, 3),TRPV1 and sodium-channels. Examples of compounds with mixed activity onmotility and pain include CRF2 antagonists, 5-HT3 antagonists oroctreotide or other molecules active at sst2 receptors.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

Conditions Hardware and Software for Analytical LCMS Systems (I)Hardware Agilent 1100 Gradient Pump Agilent 1100 Autosampler Agilent1100 DAD Dectector Agilent 1100 Degasser Agilent 1100 Oven Agilent 1100Controller Waters ZQ Mass Spectrometer Sedere Sedex 55, Sedere Sedex 85or Polymer Labs PL-ELS-2100 Software

Waters MassLynx version 4.0 SP2

Column

The column used is a Waters Atlantis, the dimensions of which are 4.6mm×50 mm. The stationary phase particle size is 3 μm.

Solvents

A: Aqueous solvent=Water+0.05% Formic AcidB: Organic solvent=Acetonitrile+0.05% Formic Acid

Method

The generic method used has a 5 minute runtime.

Time/min % B 0 3 0.1 3 4 97 4.8 97 4.9 3 5.0 3

Flow rate

The above method has a flow rate of 3 ml/mins

(II) Hardware Waters Acquity Binary Solvent Manager Waters AcquitySample Manager Waters Acquity PDA Waters ZQ Mass Spectrometer SedereSedex 85, Sedere Sedex 75, Polymer Labs PL-ELS-2100 Software

Waters MassLynx version 4.1

Column

The column used is a Waters Acquity BEH UPLC C18, the dimensions ofwhich are 2.1 mm×50 mm. The stationary phase particle size is 1.7 μm.

Solvents

A: Aqueous solvent=Water+0.05% Formic AcidB: Organic solvent=Acetonitrile+0.05% Formic Acid

Weak Wash=1:1 Methanol:Water Strong Wash=Water Method

The generic method used has a 2 minute runtime.

Time/min % B 0 3 0.1 3 1.5 97 1.9 97 2.0 3

-   -   The above method has a flow rate of 1 ml/min.    -   The injection volume for the generic method is 0.5 ul    -   The column temperature is 40 deg    -   The UV detection range is from 220 to 330 nm

Conditions for Open Access Mass Directed Auto Prep System (MDAP)Hardware

Open Access Mass Directed Prep instruments consist of the following:1 Waters 600 Gradient pump1 Waters 2767 inject/collector1 Waters Reagent manager

1 MicroMass ZQ Mass Spectrometer

1 Gilson Aspec—waste collector1 Gilson 115 post-fraction UV detector

1 Computer System. Software MicroMass MassLynx v4.0 Column

The column used is typically a Supelco LCABZ++ column whose dimensionsare 20 mm internal diameter by 100 mm in length. The stationary phaseparticle size is 5 μm.

Solvents

A:. Aqueous solvent=Water+0.1% Formic AcidB Organic solvent=MeCN:Water 95:5+0.05% Formic AcidMake up solvent=MeOH:Water 80:20+50 mMol Ammonium AcetateNeedle rinse solvent=MeOH: Water:DMSO 80:10:10

Methods

One of five methods may be used depending on the analytical retentiontime of the compound of interest.

All have a 15-minute runtime, which comprises of a 10-minute gradientfollowed by a 5-minute column flush and re-equilibration step.

MDP 1.5−2.2=0-30% B MDP 2.0−2.8=5-30% B MDP 2.5−3.0=15-55% B MDP2.8−4.0=30-80% B MDP 3.8−5.5=50-90% B Flow Rate

All of the above methods have a flow rate of 20 mL/min.

(II) Hardware Waters 2525 Binary Gradient Module Waters 515 Makeup PumpWaters Pump Control Module Waters 2767 Inject Collect Waters ColumnFluidics Manager Waters 2996 Photodiode Array Detector Waters ZQ MassSpectrometer

Gilson 202 fraction collectorGilson Aspec waste collector

Software

Waters MassLynx version 4 SP2

Column

The columns used are Waters Atlantis, the dimensions of which are 19mm×100 mm (small scale) and 30 mm×100 mm (large scale). The stationaryphase particle size is 5 μm.

Solvents

A: Aqueous solvent=Water+0.1% Formic AcidB: Organic solvent=Acetonitrile+0.1% Formic AcidMake up solvent=Methanol:Water 80:20Needle rinse solvent=Methanol

Methods

There are five methods used depending on the analytical retention timeof the compound of interest. They have a 13.5-minute runtime, whichcomprises of a 10-minute gradient followed by a 3.5 minute column flushand re-equilibration step.

Large/Small Scale 1.0−1.5=5-30% B Large/Small Scale 1.5−2.2=15-55% BLarge/Small Scale 2.2−2.9=30-85% B Large/Small Scale 2.9−3.6=50-99% B

Large/Small Scale 3.6−5.0=80-99% B (in 6 minutes followed by 7.5 minutesflush and re-equilibration)

Flow Rate

All of the above MDAP methods have a flow rate of either 20 mls/min(Small Scale) or 40 mls/min (Large Scale).

Shallow Gradients

Large 1.5 to 2.3 min=13-29% BLarge 1.9 to 2.3 min=25-41% BLarge 2.3 to 2.6 min=37-53% BLarge 2.6 to 3.1 min=49-65% BLarge 3.1 to 3.6 min=61-77% BConditions used for NMR

Hardware Bruker 400 MHz Ultrashield Bruker B-ACS60 Autosampler BrukerAdvance 400 Console Bruker DPX250 Bruker AVANCE 500 Bruker DRX600Software

User interface—NMR KioskControlling software—XWin NMR version 3.0

Chromatography

Unless stated otherwise, all column chromatography was carried out usingsilica columns.

Abbreviations

BINAP—(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthaleneBOC—tert-butyloxycarbonyl^(t)BuOH—tert-butanolCCl₄—carbon tetrachlorideCDCl₃—deuteriochloroformCuCl—copper (I) chloride1,2-DCE—1,2-dichloroethane,DCM—dichloromethaneDibal-H—di-isobutyl aluminium hydrideDME—1,2-dimethoxyethane

DMF—N,N-dimethylformamide

DMSO—dimethyl sulfoxideDMSO-d₆—dimethyl sulfoxide-d6Et₂O—diethyl etherEtOAc—ethyl acetateEtOH—ethanolHCl—hydrochloric acid, hydrogen chlorideHOBt—1-hydroxybenzotriazoleH₂SO₄—sulfuric acidKOH—potassium hydroxideMeOH—methanolMgSO₄—magnesium sulfateMnO₂—manganese dioxideNaCl—sodium chlorideNaHCO₃—sodium hydrogen carbonateNalO₄—sodium periodateNaOH—sodium hydroxideNa₂SO₄—sodium sulfateNH₃—ammoniaPd/C—palladium on charcoal

PS—Trisamine

Pt/C—platinum on charcoalSCX—strong cation exchangerTFA—trifluoroacetic acidTHF—tetrahydrofuranTHMD—2,2,6,6-tetramethyl 3,5-heptanedioneXantphos—4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Description 1 1,1-Dimethylethyl(2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1)

A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate hydrochloride (21.3 g, 0.09 mol),triethylamine (15 mL, 0.108 mol) and sodium tri(acetoxy)borohydride(42.4 g, 0.2 mol) in 1,2-DCE (500 mL) was stirred at room temperatureovernight. Saturated aqueous NaHCO₃ solution (200 mL) was added and themixture stirred for 20-30 minutes. The phases were separated and theaqueous phase was washed with DCM. The combined organics were washedwith brine, dried and concentrated. Column chromatography eluting with0-20% EtOAc/hexane gave the title compound as a pale yellow oil whichcrystallized on standing (25.61 g). δ_(H) (CDCl₃, 400 MHz) 8.19 (2H, d),7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d),3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m),1.46 (9H, s), 1.25 (3H, d).

Description 1: Alternative Method (A) 1,1-Dimethylethyl(2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1)

A mixture of 4-nitrobenzaldehyde (30.22 g, 0.2 mol), 1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (40.06 g, 0.2 mol) and sodiumtri(acetoxy)borohydride (85 g, 0.4 mol) in 1,2-DCE (1 L) was stirred atroom temperature over-weekend. The reaction mixture was treatedportion-wise with NaHCO₃ solution (400 mL) over a period of ˜2 h. Aftera further 30 mins, the organic layer was separated, washed with brine,dried and concentrated to give a viscous pale yellow oil. Purificationby column chromatography eluting with 0%, 10% and then 20% EtOAc/hexaneyielded the title compound as a yellow crystalline solid (61.1 g).

Description 2 1,1-Dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)

To 1,1-dimethylethyl(2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1)(4.62 g, 13.78 mmol) and KOH (7.79 g, 138.8 mmol) in MeOH (100 mL) wasadded wet (50% w/w water) 10% Pd/C catalyst (4 g) and the mixture washydrogenated at room temperature and atmospheric pressure for 40 mins.The catalyst was removed by filtration and the filtrate concentrated invacuo. The residue was partitioned between DCM and water and aqueouslayer was further extracted with DCM (×2). The combined organics werewashed with brine, dried and concentrated to give the title compound asa colourless gum (4.14 g) which was used in the next step withoutfurther purification. δ_(H) (CDCl₃, 400 MHz) 7.10 (2H, d), 6.64 (2H, d),4.16 (1H, br.s), 3.78 (1H, d), 3.62 (2H, s), 3.42 (1H, d), 3.28 (1H, d),3.08 (1H, td), 2.74 (1H, m), 2.58 (1H, m), 2.06 (1H, dd), 1.95 (1H, m),1.46 (9H, s), 1.21 (3H, d).

Description 2: Alternative Method (A)

1,1-Dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)

To 1,1-dimethylethyl(2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1) (15g, 44.8 mol) in MeOH (150 mL) and water (150 mL) at 80° C. was addedammonium chloride (11.9 g, 0.224 mol) and iron powder (7.5 g, 0.134 mol)with vigorous stirring. The reaction was stirred at 80° C. for 2 h thenfiltered through Celite®while still hot and the filter cake was washedwith further DCM. The filtrate layers were separated and the aqueouslayer was washed with DCM (×3). The DCM layers were combined, dried(Na₂SO₄) and concentrated to give the crude product which was purifiedby column chromatography. Elution with 20-70% EtOAc/petroleum ether gavethe title compound as a white solid (9.46 g).

Description 2: Alternative Method (B)

1,1-Dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)

A mixture of 1,1-dimethylethyl(2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D1)(21.62 g, 0.0644 mol), triethylamine (40 mL) and 5% Pt/C catalyst (21 g,56% w/w water) in MeOH (400 mL) was hydrogenated at room temperature andatmospheric pressure overnight. The catalyst was removed by filtrationand washed with further MeOH. The filtrate was concentrated,re-dissolved in DCM (200 mL) and washed with 2M NaOH solution. Theaqueous wash was re-extracted with DCM (×2, 100 mL) and all organicphases were combined, washed with brine, dried and concentrated to givethe title compound (19.53 g) which was used in the next step withoutfurther purification.

Description 3 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3)

To 1,1-dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(4.14 g, 13.56 mmol) in dry MeOH (80 mL) at 50° C. under an argonatmosphere was added paraformaldehyde (1.22 g, 40.67 mmol) and sodiummethoxide (3.65 g, 67.78 mmol). The mixture was stirred for ˜24 h thensodium borohydride (1.54 g, 40.67 mmol) was added portion-wise and thereaction stirred at 50° C. overnight. After cooling to room temperature,acetone (10 mL) was added and the solvent removed in vacuo. The residuewas partitioned between DCM and water and the organic phase was washedwith brine, then dried and concentrated. Column chromatography gave thetitle compound as a colourless, crystalline solid (3.73 g). δ_(H)(CDCl₃, 400 MHz) 7.13 (2H, d), 6.57 (2H, d), 4.16 (1H, br.s), 3.78 (1H,d), 3.67 (1H, br.s), 3.42 (1H, d), 3.30 (1H, d), 3.08 (1H, td), 2.83(3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.06 (1H, dd), 1.94 (1H, m), 1.45(9H, s), 1.21 (3H, d).

Description 3: Alternative Method (A) 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3)

A mixture of 1,1-dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(7.45 g, 24.43 mmol), paraformaldehyde (2.202 g, 73.28 mmol) and sodiummethoxide (6.597 g, 122.13 mmol) in methanol (150 mL) under an argonatmosphere was heated at 50° C. over-weekend. After cooling, sodiumborohydride (1.848 g, 48.85 mmol) was added and the reaction mixture washeated at 50° C. for 1 h then cooled to room temperature. Acetone wasadded until no more bubbling was observed, then the mixture wasconcentrated. The residue was partitioned between DCM and water and theaqueous was re-extracted with DCM. The combined organics were dilutedwith MeOH (approx. 20 mL) to aid solubility, dried and concentrated toyield the title compound as an off white solid (7.77 g)

Description 3: Alternative Method (B) 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3)

1,1-Dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(19.53 g, 0.0639 mol) in dry MeOH (300 mL) under an argon atmosphere atroom temperature was treated with paraformaldehyde (5.76 g, 0.1918 mol)and sodium methoxide (17.27 g, 0.3197 mol). The reaction mixture heatedat 50° C., stirred overnight then cooled to room temperature. Sodiumborohydride (7.26 g, 0.1918 mmol) was added portionwise and the reactionmixture was then re-heated to 50° C. and stirred for 2 days. Thereaction mixture was cooled to rt and stirred for a further 24 h, thenconcentrated and re-dissolved in DCM (200 mL). Saturated aq. NaHCO₃solution (200 mL) was added portionwise with stirring and on completionof addition the mixture was stirred at room temperature for a further0.5 h. The DCM phase was separated, washed with brine, dried (MgSO₄) andconcentrated to give a yellow oil which was purified by columnchromatography. Elution with 0%, 10% and then 20% EtOAc/hexane yieldedthe title compound as a yellow oil which crystallised on standing (16.7g).

Description 4 1,1-Dimethylethyl(2R)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D4)

The title compound was prepared from 4-nitrobenzaldehyde and1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate hydrochlorideusing a method similar to that described for D1 in Description 1. MS(ES⁺): 280.2, 236.3, no molecular ion (MH⁺) observed

Description 5 1,1-Dimethylethyl(2R)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D5)

The title compound was prepared from 1,1-dimethylethyl(2R)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D4)using a method similar to that described for D2 in Description 2although aq. 2M KOH solution was used in place of solid KOH and thereaction time was 40 minutes. MS (ES): MH⁺ 306.2, MNa⁺ 328.2.

Description 6 1,1-Dimethylethyl(2R)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D6)

The title compound was prepared from 1,1-dimethylethyl(2R)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D5)using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. for 48 h prior to addition ofsodium borohydride. δ_(H) (CDCl₃, 400 MHz) 7.13 (2H, d), 6.57 (2H, d),4.16 (1H, m), 3.78 (1H, d), 3.42 (1H, d), 3.29 (1H, d), 3.08 (1H, td),2.83 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.07 (1H, dd), 1.94 (1H, m),1.45 (9H, s), 1.21 (3H, d). MS (ES⁺): 342.3 (MNa⁺), 220.2, no molecularion (MH⁺) observed.

Description 7 1,1-Dimethylethyl(2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate(D7)

The title compound may be prepared using a method similar to thatdescribed for D1.

Description 7: Alternative Method (A) 1,1-Dimethylethyl(2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate(D7)

(3R,5S)-1-[(4-Nitrophenyl)methyl]-3,5-dimethylpiperazine (D82) (4.278 g,17.17 mmol) was dissolved in dioxane (180 mL) and Boc anhydride (7.494g, 34.34 mmol) and saturated aqueous NaHCO₃ solution (60 mL) were added.The mixture was stirred at room temperature overnight; the mixture wasfiltered and the filter cake washed with DCM. The filtrate wasconcentrated under vacuum and the residue partitioned between DCM andwater. The DCM layer was separated and the aqueous was extracted withDCM (×2). The DCM layers were combined and dried to produce a yellow oil(9.614 g). The mixture was purified by passing through an SCX cartridgeto produce a yellow oil (4.787 g) which was a mixture of the titlecompound and unreacted D82. This whole was dissolved in DCM (60 mL) andtriethylamine (2.936 mL) added followed by Boc anhydride (4.612 g, 21.13mmol). The mixture was stirred at room temperature overnight underargon. PS Trisamine® (6 g) was added and the mixture allowed to stir for30 min; the polymer was filtered off and the solvent removed to producea yellow oil (6.5621 g). Purification by column chromatography elutingwith 0-50% Et₂O/petroleum ether gave a pale yellow solid (5.245 g). Thissolid was dissolved in MeOH and passed down an SCX cartridge (70 g)which was flushed with MeOH followed by 2MNH₃ in MeOH. The solvent wasremoved to produce a yellow solid (3.833 g) which was further purifiedby column chromatography. Elution with 0-50% Et₂O/petroleum ether gavethe title compound as a whitish cream solid (2.624 g). MS (ES⁺): 294.3,250.3, no molecular ion (MH⁺) observed.

Description 8 1,1-Dimethylethyl(2R,6S)-4-[(4-aminophenyl)methyl]-2,6-dimethyl-1-piperazinecarboxylate(D8)

To a solution of 1,1-dimethylethyl(2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate(D7) (2.62 g, 7.53 mmol) in MeOH (25 mL) and water (25 mL) heated to 80°C. was added iron powder (1.26 g, 22.54 mmol) and ammonium chloride(2.01 g, 37.58 mmol). The reaction was stirred vigorously at 80° C. for1.5 h and then the iron residues removed by filtration through Celite®.The filtrate was concentrated and the residue partitioned between DCMand water. The aqueous layer was further extracted with DCM (×2) and thecombined organics were dried and concentrated to give the crude productas a yellow foam (2.01 g). Column chromatography eluting with 0-100%Et₂O/petroleum ether gave the title compound (1.694 g). δ_(H) (CDCl₃,400 MHz) 7.12 (2H, d), 6.64 (2H, d), 4.05 (2H, m), 3.64 (2H, br s), 3.36(2H, s), 2.59 (2h, d), 2.06 (2H, dd), 1.46 (9H, s), 1.27 (6H, d). MS(ES): MH⁺ 320.3, MNa⁺ 342.3.

Description 9 1,1-Dimethylethyl(2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D9)

The title compound was prepared from 1,1-dimethylethyl(2R,6S)-4-[(4-aminophenyl)methyl]-2,6-dimethyl-1-piperazinecarboxylate(D8) using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. for 48 h prior to addition ofsodium borohydride then for 1 h after addition. Further paraformaldehyde(1 eq) and sodium methoxide (1 eq) were added; the reaction was heatedat 50° C. for 12 h; further sodium borohydride (1 eq) was added and thereaction heated at 50° C. for 1 h. δ_(H) (CDCl₃, 400 MHz) 7.16 (2H, d),6.57 (2H, d), 4.05 (2H, m), 3.70 (1H, br s), 3.36 (2H, s), 2.82 (3H, s),2.59 (2H, d), 2.06 (2H, dd), 1.49 (9H, s), 1.27 (6H, d). MS (ES⁺): 356.3(MNa⁺), 234.3, no molecular ion (MH⁺) observed.

Description 10 1,1-Dimethylethyl4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D10)

The title compound was prepared from 4-nitrobenzaldehyde and1,1-dimethylethyl 1-piperazinecarboxylate using a method similar to thatdescribed for D1 in Description 1A although the product was purified bycolumn chromatography followed by passing through an SCX column elutingwith MeOH then 2M NH₃ in MeOH. MS (ES⁺): 266.1, 222.2, no molecular ion(MH⁺) observed.

Description 11 1,1-Dimethylethyl4-[(4-aminophenyl)methyl]-1-piperazinecarboxylate (D11)

The title compound was prepared from D10 using a method similar to thatdescribed for D8 in Description 8 although no column chromatography wasrequired. MS (ES): MH⁺ 292.1, MNa⁺ 314.2.

Description 12 1,1-Dimethylethyl4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D12)

The title compound was prepared from D11 using a method similar to thatdescribed for D3 in Description 3A although the reaction was heated at50° C. overnight prior to addition of sodium borohydride and no columnchromatography was required. δ_(H) (CDCl₃, 400 MHz) 7.11 (2H, d), 6.57(2H, d), 3.69 (1H, br.s), 3.40 (6H, m), 2.83 (3H, s), 2.36 (4H, m), 1.45(9H, s) [δ values corrected for incorrectly referenced TMS at 0.58 ppmon spectrum]. MS (ES⁺): 206.2, no molecular ion (MH⁺) observed.

Description 13 Ethyl 6-[(4-fluorophenyl)oxy]-3-pyridinecarboxylate (D13)

Sodium hydride (0.653 g, 60% in mineral oil, 16.338 mmol) was suspendedin DMF (10 mL) under argon, and 4-fluorophenol (0.915 g, 8.169 mmol)added in two portions. The mixture was stirred for 20 minutes then ethyl6-chloro-3-pyridinecarboxylate (1.515 g, 8.169 mmol) was added togetherwith additional DMF (4 mL) added to aid solubility. The mixture washeated to 80° C. for 2.5 h. The reaction mixture was allowed to cool toroom temperature and water (30 mL) was added. The solution was acidifiedto pH 3 with 2M HCl and extracted with ethyl acetate (×3). The combinedethyl acetate layers were dried and concentrated to produce a brown oil.The crude product was purified by chromatography. Elution with a 0-25%Et₂O/petroleum ether gradient gave the title compound as a colourlessoil (0.284 g). δ_(H) (CDCl₃, 400 MHz) 8.81 (1H, dd), 8.28 (1H, dd), 7.11(4H, m), 6.95 (1H, d), 4.37 (2H, q), 1.38 (3H, t). MS (ES): MH⁺ 262.2.

Description 14 6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14)

Ethyl 6-[(4-fluorophenyl)oxy]-3-pyridinecarboxylate (D13) (0.275 g,1.054 mmol) was taken up in 1,4-dioxane (5 mL) and lithium hydroxide(0.050 g, 2.109 mmol) was dissolved in water. The two solutions werecombined and stirred at room temperature for 2 h. The mixture wasacidified to pH 5 with 2M HCl and concentrated. The residue was taken upin ethyl acetate, dried and concentrated to yield the title compound asa cream/white solid (0.233 g). δ_(H) (DMSO-d₆, 400 MHz) 13.20 (1H, bs),8.65 (1H, dd), 8.28 (1H, dd), 7.26 (4H, m), 7.12 (1H, d). MS (ES): MH⁺234.2, (M-H⁺) 232.1.

Description 14: Alternative Method (A)6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14)

A mixture of 4-fluorophenol (96.8 g), methyl6-chloropyridine-3-carboxylate (30 g) and cesium carbonate (285.3 g) inDMSO (875 mL) was stirred and heated to 130° C. over a period of 1.75 hthen cooled overnight. The reaction mixture was reheated to ˜150° C.over a period of 1.5 h, kept at this temperature for ˜1 h, then cooledto ˜40° C. and poured into water (4 L). The aqueous solution wasextracted with ether (1.0 L) then adjusted to pH7-8 by addition of 2MHCl. The solution was extracted with further ether (2×1.0 L), thenadjusted to pH 2 by addition of 2M HCl causing precipitation of a solid.The precipitate was collected by filtration, washed with water and driedovernight at 40° C. in vacuo to give the title compound as a beige/pinksolid (36.7 g).

Description 15 1,1-Dimethylethyl(2R,6S)-4-({4-[{[6-(4-fluorophenyl)-2-methyl-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2,6-dimethyl-1-piperazinecarboxylate(D15)

Step 1: 6-(4-Fluorophenyl)-2-methyl-3-pyridinecarboxylic acid (0.2 g,0.866 mol) was suspended in DCM (14 mL) and DMF (1 drop) was added. Themixture was cooled in an ice-bath and oxalyl chloride (0.226 mL, 2.598mmol) was added portion wise over 5 minutes. The mixture was heated to40° C. for 90 minutes. The mixture was allowed to cool and the solventremoved under vacuum to give6-(4-fluorophenyl)-2-methyl-3-pyridinecarbonyl chloride as a yellowsolid (0.270 g) which was used directly in step 2.

Step 2: The acid chloride from step 1 was taken up in DCM (3 mL) andadded to a solution of 1,1-dimethylethyl(2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D9) (0.23 g, 0.693 mmol) in DCM (2 mL). Triethylamine (0.193 mL, 1.386mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with DCM and washed withwater. The aqueous layer was re-extracted with DCM (×2) and the combinedorganics were dried and concentrated. The crude product was purified bycolumn chromatography. Elution with 0-50% EtOAc/petroleum yielded thetitle compound as a white foam (0.331 g). δ_(H) (CDCl₃, 400 MHz) 7.89(2H, m), 7.36 (1H, m), 7.26 (1H, m), 7.19 (2H, m), 7.10 (2H, t), 6.99(2H, m), 4.00 (2H, m), 3.53 (3H, s), 3.34 (2H, s), 2.58 (3H, s), 2.44(2H, d), 2.05 (2H, m), 1.44 (9H, s), 1.18 (6H, d). MS (ES): MH⁺ 547.3.

Description 16 1,1-Dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16)

Step 1: 6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (0.232g, 0.994 mmol) was dissolved in 1,4-dioxane (6 mL) and thionyl chloride(0.363 mL, 4.972 mmol) added dropwise. The mixture was heated at refluxfor 3.5 h, then cooled and concentrated in vacuo. DCM was added to theresidue which was then re-concentrated to yield6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride as a yellow oil(0.252 g) which was used directly in step 2.

Step 2: The acid chloride from step 1 was taken up in DCM (3 mL) andadded to 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.288 g, 0.904 mmol) in DCM (3 mL). Triethylamine (0.251 mL, 1.808mmol) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM and washed withwater. The aqueous was extracted with DCM (×2) and the combined organiclayers were dried and concentrated. The crude product was purified bycolumn chromatography. Elution with a 0-50% EtOAc/petroleum ethergradient gave the title compound as a colourless oil (0.518 g). δ_(H)(CDCl₃, 400 MHz) 8.07 (1H, m), 7.65 (1H, dd), 7.24 (2H, d), 7.03 (6H,m), 6.70 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H,d), 3.34 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.50 (1H, d), 2.10 (1H,dd), 2.00 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH⁺ 535.3.

Description 16: Alternative Method (A) 1,1-Dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16)

6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (20.1 g, 0.0862mol) was dissolved in 1,4-dioxane (400 mL) and thionyl chloride (28.5mL, 4.972 mmol) added cautiously. The mixture was heated slowly toreflux and stirred for 4.5 h. The reaction mixture was allowed to cooland concentrated. Dioxane (200 mL) was added and the solution wasre-concentrated (×2) to give crude6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride which wasre-dissolved in DCM (250 mL). This was added dropwise to a solution of1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (25 g, 0.0783 mol, prepared in three different batches according tomethod D3B and consolidated) and triethylamine (14 mL, 0.1004 mol) inDCM (250 mL) cooled in an ice/water bath over 30 mins. The reactionmixture was warmed to room temperature and stirred for ˜15 h. Thereaction mixture was washed with 2M NaOH solution (2×200 mL) and brine,then dried over MgSO₄ and concentrated in vacuo to give a brownfoam/gum. The crude product was purified by chromatography to give thetitle compound as a colourless foam (32.39 g).

Tabulated compounds D17, D40 and D41 were prepared using methods similarto those described in Description 15 using the appropriate anilineprecursor and appropriate carboxylic acid.

Tabulated compounds D18-D53 (excepting D40 and D41) were prepared usingmethods similar to those described in Description 16 using theappropriate aniline precursor and appropriate carboxylic acid.

Aniline Description precursor Structure D17 D3

D18 D3

D19 D3

D20 D2

D21 D3

D22 D3

D23 D3

D24 D3

D25 D3

D26 D3

D27 D3

D28 D3

D29 D3

D30 D3

D31 D3

D32 D3

D33 D3

D34 D9

D35 D3

D36 D3

D37 D3

D38 D3

D39 D3

D40 D6

D41 D6

D42 D3

D43 D3

D44 D3

D45 D12

D46 D12

D47 D81

D48 D3

D49 D3

D50 D64

D51 D3

D52 D3

D53 D67

Method Comment Description Name Step 1 Step 2 MH+ D17 1,1-dimethylethyl(2S)-4-({4- Similar method to D15 Similar method to D15 519.2[{[6-(4-fluorophenyl)-3- although reaction although additionalpyridinyl]carbonyl}(methyl)amino] temp./time: 0° C./ purification byMDAP phenyl}methyl)-2-methyl-1- 20 mins then room piperazinecarboxylatetemperature/1 h D18 1,1-dimethylethyl (2S)-2-methyl- Similar method toD16 Similar method to D16 510 4-{[4-(methyl{[6-(4- although reactionalthough reaction time: morpholinyl)-3- temp./time: room over-weekendpyridinyl]carbonyl}amino)phenyl] temperature, overnightmethyl}-1-piperazinecarboxylate D19 1,1-dimethylethyl (2S)-4-({4-[[(4′-Similar method to D16 Similar method to D16 518.2 fluoro-4- althoughreaction although reaction time: biphenylyl)carbonyl](methyl)temp./time: room over-weekend amino]phenyl}methyl)-2-methyl-1-temperature, overnight piperazinecarboxylate then, reflux, 3 h D201,1-dimethylethyl (2S)-4-{[4-({[6- Similar method to D16 Similar methodto D16 519.4 (4-fluorophenyl)-2-methyl-3- although reactionpyridinyl]carbonyl}amino)phenyl] temp./time: room methyl}-2-methyl-1-temperature, ~3 h piperazinecarboxylate D21 1,1-dimethylethyl(2S)-4-({4-[({1- Similar method to D16 Similar method to D16 553.3[(3-fluorophenyl)carbonyl]-4- although reactionpiperidinyl}carbonyl)(methyl) temp./time: roomamino]phenyl}methyl)-2-methyl-1- temperature, ~0.5 hpiperazinecarboxylate D22 1,1-dimethylethyl (2S)-4-({4-[({1- Similarmethod to D16 Similar method to D16 539.3 [(3-fluorophenyl)methyl]-4-although reaction although reaction time: piperidinyl}carbonyl)(methyl)temp./time: room over-weekend amino]phenyl}methyl)-2-methyl-1-temperature, 1 h piperazinecarboxylate D23 1,1-dimethyethyl(2S)-4-({4-[{[1- Similar method to D16 Similar method to D16 541.4(4-chlorophenyl)-4- although reaction piperidinyl]carbonyl}(methyl)temp./time: room amino]phenyl}methyl)-2-methyl-1- temperature, 1 hpiperazinecarboxylate D24 1,1-dimethylethyl (2S)-2-methyl- Similarmethod to D16 Similar method to D16 508.44-{[4-(methyl{[6-(1-piperidinyl)-3- although reaction although reactiontime: pyridinyl]carbonyl}amino)phenyl] temp: room 1 hmethyl}-1-piperazinecarboxylate temperature, D25 1,1-dimethylethyl(2S)-4-({4-[{[6- Similar method to D16 Similar method to D16 519.2(2-fluorophenyl)-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 40 mins. phenyl}methyl)-2-methyl-1-piperazinecarboxylate D26 1,1-dimethylethyl (2S)-4-({4-[{[6- Similarmethod to D16 Similar method to D16 551.3(2,4-difluorophenyl)-2-methyl-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 1.5 h. phenyl}methyl)-2-methyl-1-piperazinecarboxylate D27 1,1-dimethylethyl (2S)-4-({4-[{[6- Similarmethod to D16 Similar method to D16 551.3(3,4-difluorophenyl)-2-methyl-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 0.75 h. phenyl}methyl)-2-methyl-1-piperazinecarboxylate D28 1,1-dimethylethyl (2S)-4-({4-[{[6- Similarmethod to D16 Similar method to D16 533.2 (3-fluorophenyl)-2-methyl-3-although reaction time: pyridinyl]carbonyl}(methyl)amino] 0.75 h.phenyl}methyl)-2-methyl-1- piperazinecarboxylate D29 1,1-dimethylethyl(2S)-4-({4-[({4- Similar method to D16 Similar method to D16 534.3 [(3-although reaction although reaction time:fluorophenyl)oxy]phenyl}carbonyl) temp./time: room 4 h(methyl)amino]phenyl}methyl)-2- temperature,methyl-1-piperazinecarboxylate 4 h; 50° C., 3 h, 100° C., overnight D301,1-dimethylethyl (2S)-4-({4-[{[6- Similar method to D16 Similar methodto D16 540.3 (3-cyanophenyl)-2-methyl-3- although reaction time:although reaction time: pyridinyl]carbonyl}(methyl)amino] 3 h.over-weekend phenyl}methyl)-2-methyl-1- piperazinecarboxylate D311,1-dimethylethyl (2S)-4-({4-[{[6- Similar method to D16 Similar methodto D16 540.3 (4-cyanophenyl)-2-methyl-3- although reaction time:although reaction time: pyridinyl]carbonyl}(methyl)amino] 3 h.over-weekend phenyl}methyl)-2-methyl-1- piperazinecarboxylate D321,1-dimethylethyl (2S)-4-({4-[({4- Similar method to D16 Similar methodto D16 534.2 [(4- although reaction although reaction time:fluorophenyl)oxy]phenyl}carbonyl) temp./time: 100°C., over-weekend(methyl)amino]phenyl}methyl)-2- overnight methyl-1-piperazinecarboxylateD33 1,1-dimethylethyl (2S)-4-({4-[({2- Similar method to D16 Similarmethod to D16 534.2 [(4- although reaction although reaction time:fluorophenyl)oxy]phenyl}carbonyl) temp./time: 100° C., over-weekend(methyl)amino]phenyl}methyl)-2- overnight methyl-1-piperazinecarboxylateD34 1,1-dimethylethyl (2R,6S)-4-({4- Similar method to D16 Similarmethod to D16 533.3 [{[6-(4-fluorophenyl)-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 3 h. phenyl}methyl)-2,6-dimethyl-1-piperazinecarboxylate D35 1,1-dimethylethyl (2S)-4-({4-[({4- Similarmethod to D16 Similar method to D16 534.2 [(2- although reactionalthough reaction time: fluorophenyl)oxy]phenyl}carbonyl) temp./time:100° C., 3 h and no column (methyl)amino]phenyl}methyl)-2- overnightchromatography methyl-1-piperazinecarboxylate D36 1,1-dimethylethyl(2S)-4-({4-[({3- Similar method to D16 Similar method to D16 534.2 [(4-although reaction although reaction time:fluorophenyl)oxy]phenyl}carbonyl) temp./time: 100° C., 3 h and no column(methyl)amino]phenyl}methyl)-2- overnight chromatographymethyl-1-piperazinecarboxylate D37 1,1-dimethylethyl (2S)-4-({4-[({3-Similar method to D16 Similar method to D16 534.2 [(3- although reactionalthough reaction time: fluorophenyl)oxy]phenyl}carbonyl) temp./time:100° C., 2 h and no column (methyl)amino]phenyl}methyl)-2- overnightchromatography methyl-1-piperazinecarboxylate D38 1,1-dimethylethyl(2S)-4-({4-[{[2- Similar method to D16 Similar method to D16 534.3(4-fluorophenyl)-4-methyl-5- although reaction time: although reactiontime: pyrimidinyl]carbonyl}(methyl) 1 h. 12 hamino]phenyl}methyl)-2-methyl-1- piperazinecarboxylate D391,1-dimethylethyl (2S)-4-({4-[{[2- Similar method to D16 Similar methodto D16 520.3 (4-fluorophenyl)-5- although reaction time: althoughreaction time: pyrimidinyl]carbonyl}(methyl) 1 h. 3 h and no columnamino]phenyl}methyl)-2-methyl-1- chromatography piperazinecarboxylateD40 1,1-dimethylethyl (2R)-4-({4-[{[6- Similar method to D15 Similarmethod to D15 533.3 (4-fluorophenyl)-2-methyl-3-pyridinyl]carbonyl}(methyl)amino] phenyl}methyl)-2-methyl-1-piperazinecarboxylate D41 1,1-dimethylethyl (2R)-4-({4-[{[6- Similarmethod to D15 Similar method to D15 519.3 (4-fluorophenyl)-3-pyridinyl]carbonyl}(methyl)amino] phenyl}methyl)-2-methyl-1-piperazinecarboxylate D42 1,1-dimethylethyl (2S)-4-({4-[[(4′- Similarmethod to D16 Similar method to D16 518.3 fluoro-3- although reactiontime: although reaction time: biphenylyl)carbonyl](methyl) 1 h.over-weekend amino]phenyl}methyl)-2-methyl-1- piperazinecarboxylate D431,1-dimethylethyl (2S)-4-({4-[[(4′- Similar method to D16 Similar methodto D16 518.3 fluoro-2- although reaction time: although reaction time:biphenylyl)carbonyl](methyl) 1 h. over-weekendamino]phenyl}methyl)-2-methyl-1- piperazinecarboxylate D441,1-dimethylethyl (2S)-4-({4-[{[6- Similar method to D16 Similar methodto D16 541.3 (2-cyanophenyl)-2-methyl-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 1 h. phenyl}methyl)-2-methyl-1-piperazinecarboxylate D45 1,1-dimethylethyl 4-({4-[{[6-(3- Similarmethod to D16 Similar method to D16 505.3 fluorophenyl)-3- althoughreaction although reaction time: pyridinyl]carbonyl}(methyl) temp./time:100° C., 4 h amino]phenyl}methyl)-1- 1 h piperazinecarboxylate D461,1-dimethylethyl 4-({4-[{[6-(3- Similar method to D16 Similar method toD16 519.3 fluorophenyl)-2-methyl-3- carried out at roompyridinyl]carbonyl}(methyl) temperature, over- amino]phenyl}methyl)-1-night; then 50° C., piperazinecarboxylate 2 h. Extra thionyl chloride (2eq.) was added, then heated at 50° C., 2 h and 75° C., 2 h. D471,1-dimethylethyl (2S)-4-({4-[{[6- Similar method to D16 Similar methodto D16 533.3 (3-fluorophenyl)-3- although reaction time: althoughreaction time: pyridinyl]carbonyl}(methyl) 1.5 h. 4 daysamino]-2-methylphenyl}methyl)-2- methyl-1-piperazinecarboxylate D481,1-dimethylethyl (2S)-4-({4-[{[6- Similar method to D16 Similar methodto D16 526.3 (3-cyanophenyl)-3- although reaction time:pyridinyl]carbonyl}(methyl)amino] 1.25 h. phenyl}methyl)-2-methyl-1-piperazinecarboxylate D49 1,1-dimethylethyl (2S)-4-({4-[{[6- Similarmethod to D16 Similar method to D16 526.2 (2-cyanophenyl)-3- althoughreaction time: pyridinyl]carbonyl}(methyl)amino] 1.25 h.phenyl}methyl)-2-methyl-1- piperazinecarboxylate D50 1,1-dimethylethyl(2S)-4-({3- Similar method to D16 Similar method to D16 537.1fluoro-4-[{[6-(3-fluorophenyl)-3- although reaction time: but no aq.work-up. pyridinyl]carbonyl}(methyl)amino] 1-2 h. Concentrated reactionphenyl}methyl)-2-methyl-1- mixture purified piperazinecarboxylatedirectly by column chromatography D51 1,1-dimethylethyl (2S)-4-({4-[({1-Similar method to D16 Similar method to D16 557.2[(3,4-difluorophenyl)methyl]-4- although reaction time:piperidinyl}carbonyl)(methyl) ~1 h. amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate D52 1,1-dimethylethyl (2S)-4-({4-[({1- Similarmethod to D16 Similar method to D16 539.9 [(4-fluorophenyl)methyl]-4-although reaction time: although reaction time:piperidinyl}carbonyl)(methyl) 50 mins. ~1.5 daysamino]phenyl}methyl)-2-methyl-1- piperazinecarboxylate D531,1-dimethylethyl (2S)-4-({2- Similar method to D16 Similar method toD16 537.2 fluoro-4-[{[6-(3-fluorophenyl)-3- although reaction time:although reaction time: pyridinyl]carbonyl}(methyl)amino] 1-2 h.over-weekend. No aq. phenyl}methyl)-2-methyl-1- work-up-reactionpiperazinecarboxylate mixture concentrated and purified directly bycolumn chromatography

Description 54 1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D54)

1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate(D3) (0.4 g, 1.254 mmol) was taken up in DCM (4 mL) under argon.6-Chloro-3-pyridinecarbonyl chloride (0.243 g, 1.379 mmol) in DCM (4 mL)and triethylamine (0.348 mL, 2.508 mmol) were added. The mixture wasstirred at room temperature overnight. The mixture was diluted with DCMand washed with water. The aqueous layer was extracted with DCM (×2) andthe combined organics dried and concentrated to a pale yellow oil. Thecrude product was purified by column chromatography. Elution with a0-50% EtOAc/petroleum ether gradient yielded the title compound as awhite foam/gum (0.601 g). δ_(H) (CDCl₃, 400 MHz) 8.21 (1H, d), 7.61 (1H,dd), 7.25 (2H, d), 7.16 (1H, d), 6.99 (2H, d), 4.18 (1H, br.s), 3.80(1H, d), 3.50 (3H, s), 3.47 (1H, d), 3.34 (1H, d), 3.10 (1H, td), 2.70(1H, d), 2.49 (1H, d), 2.10 (1H, dd), 2.00 (1H, m), 1.46 (9H, s), 1.20(3H, d). MS (ES): MH⁺ 459.2.

Description 55 1,1-Dimethylethyl(2S)-4-({4-[({6-[(2-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

-   -   (D55)

1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D54) (0.1 g, 0.218 mmol) and 2-fluorophenol (0.025 g, 0.436 mmol) weredissolved in DMF (5 mL). Potassium carbonate (0.06 g, 0.436 mmol) wasadded and the mixture was heated to 80° C. overnight then at 130° C. for7 h. The mixture was left to stand at room temperature overnight and thesolvent removed under vacuum. The residue was partitioned between EtOAcand water. The organic layer was dried and concentrated to produce abrown oil. The crude product was purified by MDAP to yield the formicacid salt. The salt was taken up in DCM and washed with sat. NaHCO₃. TheDCM layer was dried and concentrated to yield the title compound as acolourless oil (0.038 g). δ_(H) (CDCl₃, 400 MHz) 8.02 (1H, d), 7.68 (1H,dd), 7.23 (2H, d), 7.15 (4H, m), 6.98 (2H, d), 6.78 (1H, d), 4.18 (1H,br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.33 (1H, d), 3.08 (1H,td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.46 (9H,s), 1.20 (3H, d). MS (ES): MH⁺ 535.3.

Description 56 1,1-Dimethylethyl(2S)-4-({4-[({6-[(3-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D56)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D54) and 3-fluorophenol in a similar manner to that described for D55in Description 55, yielding the title compound as a pale yellow oil(0.057 g). MS (ES): MH⁺ 535.3.

Description 57 1,1-Dimethylethyl(2S)-4-({4-[({6-[(3-cyanophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D57)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D54) and 3-cyanophenol in a similar manner to that described for D55 inDescription 55 although the reaction temp./time was 130° C. for 24 h andpurification was carried out by column chromatography. This gave thetitle compound as a colourless oil (0.184 g). MS (ES): MH⁺ 542.3.

Description 58 1,1-Dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)amino]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D58)

BINAP (0.041 g, 0.0654 mmol), cesium carbonate (0.213 g, 0.654 mmol) andpalladium acetate (0.009 g, 0.0436 mmol) were combined in dioxane (1 mL)and sonicated for 1 h under an argon atmosphere. To the red mixture wasadded 4-fluoroaniline (0.053 g, 0.479 mmol) and 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D54) (0.2 g, 0.436 mmol). The mixture was stirred at 60° C. for 1 h,the solvent was removed under vacuum and the residues partitionedbetween EtOAc and water. The EtOAc layer was dried and concentrated. Thecrude product was purified by chromatography. Elution with a 0-70%EtOAc/petroleum ether gradient yielded the title compound as a paleyellow oil (0.110 g). δ_(H) (CDCl₃, 400 MHz) 8.10 (1H, m), 7.40 (1H,dd), 7.25 (3H, m), 7.02 (4H, m), 6.92 (1H, s), 6.43 (1H, d), 4.18 (1H,br.s), 3.80 (1H, d), 3.48 (3H, s), 3.48 (1H, d), 3.36 (1H, d), 3.10 (1H,td), 2.70 (1H, d), 2.52 (1H, d), 2.10 (1H, m), 1.98 (1H, m), 1.85 (1H,br.s), 1.45 (9H, s), 1.20 (3H, d). MS (ES): MH⁺ 534.3.

Description 59 1,1-Dimethylethyl(2S)-4-({4-[{[1-(4-fluorophenyl)-4-piperidinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D59)

Step 1: 1-(4-Fluorophenyl)-4-piperidinecarboxylic acid (0.1 g, 0.45mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.165 mL, 2.25mmol) was added drop-wise. After stirring for 1 h the solvent wasremoved by evaporation, DCM was added to the residue which was thenre-concentrated to give 1-(4-fluorophenyl)-4-piperidinecarbonyl chloridewhich was used directly in step 2.

Step 2: The acid chloride from step 1 was taken up in DCM (2.5 mL) andadded drop-wise to 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.121 g, 0.38 mmol) in DCM (2.5 mL), followed by triethylamine(0.080 mL, 0.57 mmol). The reaction mixture was stirred for 3 h underargon, then the solvent was removed by evaporation. The residue waspartitioned between DCM (30 mL) and water (30 mL). The aqueous wasre-extracted with DCM (30 mL) and the combined organic layers were driedand concentrated to yield the title compound as a yellow oil. δ_(H)(CDCl₃, 400 MHz) 7.40 (2H, d), 7.15 (2H, d), 6.89 (2H, m), 6.80 (2H, m),4.20 (1H, br.s), 3.82 (1H, d), 3.50 (4H, m), 3.27 (3H, s), 3.10 (1H, m),2.76 (1H, d), 2.58 (1H, d), 2.35 (3H, m), 2.17 (1H, m), 2.00 (3H, m),1.70 (2H, d), 1.46 (9H, s), 1.22 (3H, d). MS (ES): MH⁺ 525.4.

Description 60 1,1-Dimethylethyl(2S)-4-({4-[{[6-(3-fluorophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D60)

Step 1: 6-(3-Fluorophenyl)-3-pyridinecarboxylic acid (82 mg, 0.376 mmol)was stirred in dioxane (4 mL) and thionyl chloride (0.137 mL, 1.88 mmol)added dropwise. The reaction mixture was heated at reflux for 40 minthen concentrated in vacuo to give 6-(3-fluorophenyl)-3-pyridinecarbonylchloride as a white solid (0.088 g) which was used directly in step 2.

Step 2: The acid chloride from step 1 was taken up in DCM and addeddrop-wise to a mixture of 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.1 g, 0.313 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM(5 mL). The reaction mixture was stirred at room temperature under argonfor ˜15 h, then diluted with water and DCM. The organic layer was driedand concentrated to give the crude product, which was purified by columnchromatography. Elution with EtOAc/petroleum ether yielded the titlecompound as a yellow oil (0.127 g). δ_(H) (CDCl₃, 400 MHz) 8.51 (1H, d),7.75 (1H, dd), 7.67 (2H, m), 7.55 (1H, d), 7.40 (1H, m), 7.24 (2H, d),7.08 (1H, m), 7.03 (2H, d), 4.15 (1H, br.s), 3.78 (1H, d), 3.53 (3H, s),3.45 (1H, d), 3.32 (1H, d), 3.06 (1H, td), 2.69 (1H, d), 2.49 (1H, d),2.09 (1H, dd), 1.98 (1H, m), 1.44 (9H, s), 1.16 (3H, d). MS (ES): MH⁺519.3.

Description 61 1,1-Dimethylethyl(2S)-4-({4-[{[6-(4-fluorophenyl)-2-methyl-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D61)

To 1-hydroxybenzotriazole (63.4 mg, 0.47 mmol) andN-benzyl-N′-cyclohexylcarbodiimide resin (351.6 mg, 1.6 mmol/g) in DMF(1 mL) was added 6-(4-fluorophenyl)-2-methyl-3-pyridinecarboxylic acid(72.3 mg, 0.313 mmol) in DMF (1 mL). The mixture was stirred for 30minutes under an argon atmosphere and1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (100 mg, 0.313 mmol) in DCM (2 mL) was added. The mixture wasstirred overnight at room temperature. PS-trisamine resin (2 eq.relative to acid), PS-isocyanate resin (2 eq. relative to amine) andMP-carbonate resin (5 eq. relative to HOBt) were added and the mixturestirred overnight at room temperature. The mixture was filtered toremove the resins which were then washed with further DCM. The filtratewas concentrated to give the crude product which was purified by columnchromatography. Elution with an ether/petroleum ether gradient yieldedthe title compound (35.2 mg). δ_(H) (CDCl₃, 400 MHz) 8.00 (2H, s), 7.37(1H, d), 7.27 (1H, m), 7.12 (4H, m), 6.98 (2H, s), 4.14 (1H, bm), 3.75(2H, d), 3.52 (3H, s), 3.40 (1H, d), 3.25 (1H, d), 3.03 (1h, t), 2.58(4H, m), 2.41 (1H, d), 2.04 (1H, m), 1.95 (1H, m), 1.44 (9H, s), 1.13(3H, d). MS (ES): MH⁺ 533.3.

Description 621,1-Dimethylethyl(2S)-4-[(3-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D62)

A solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (232 mg, 1 mmol)and Hunig's base (0.192 mL, 1.1 mmol) in DMF (3 mL) was treated with1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (200 mg, 1 mmol)in DMF (3 mL) and stirred at room temperature for 20 minutes. Thereaction mixture was concentrated, re-dissolved in DCM and washed withwater and brine, then dried and concentrated. The crude product waspurified by column chromatography. Elution with EtOAc/pentane yieldedthe title compound as a colourless gum (327 mg). δ_(H) (CDCl₃, 400 MHz)8.03 (1H, m), 7.34 (1H, dd), 7.27 (1H, m), 4.22 (1H, br.s), 3.84 (1H,d), 3.58 (1H, d), 3.47 (1H, d), 3.13 (1H, td), 2.72 (1H, m), 2.54 (1H,m), 2.22 (1H, dd), 2.09 (1H, m), 1.46 (9H, s), 1.26 (3H, d) [valuescorrected for incorrectly referenced TMS at 0.62 ppm on spectrum].

Description 63 1,1-Dimethylethyl(2S)-4-[(4-amino-3-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D63)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-[(3-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D62) using a method similar to that described for D2 in Description 2although the reaction was carried out on an H-Cube™ continuous flowhydrogenator and triethylamine was used in place of solid KOH. δ_(H)(CDCl₃, 400 MHz) 6.99 (1H, dd), 6.86 (1H, dd), 6.71 (1H, dd), 4.17 (1H,br.s), 3.79 (1H, d), 3.67 (2H, br.s), 3.40 (1H, d), 3.27 (1H, d), 3.09(1H, td), 2.73 (1H, m), 2.56 (1H, m), 2.08 (1H, dd), 1.96 (1H, m), 1.45(9H, s), 1.22 (3H, d).

Description 64 1,1-Dimethylethyl(2S)-4-{[3-fluoro-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D64)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-[(4-amino-3-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D63) using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. overnight prior to and afteraddition of sodium borohydride. δ_(H) (CDCl₃, 400 MHz) 6.96 (2H, m),6.61 (1H, m), 4.17 (1H, br.s), 3.89 (1H, br.s), 3.79 (1H, d), 3.41 (1H,d), 3.28 (1H, d), 3.08 (1H, td), 2.87 (3H, s), 2.74 (1H, m), 2.57 (1H,m), 2.08 (1H, dd), 1.95 (1H, m), 1.45 (9H, s), 1.22 (3H, d).

Description 65 1,1-Dimethylethyl(2S)-4-[(2-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D65)

Step 1: A mixture of 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol),N-bromosuccinimide (1.96 g, 11 mmol) and benzoyl peroxide (0.121 g, 0.5mmol) in CCl₄ (60 mL) was irradiated with a 500 W lamp overnight. Thereaction mixture was filtered, concentrated and eluted through a silicacolumn with EtOAc/pentane to give a crude product mixture (2.34 g) whichwas used in step 2.

Step 2: A mixture of crude 4-(bromomethyl)-3-fluoro-1-nitrobenzene (2.11g) from step 1, Hunig's base (1.9 mL, 10.913 mmol) and 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (2 g, 10 mmol) in DMF (15 mL) wasstirred at room temperature for 40 minutes. The reaction mixture wasconcentrated, re-dissolved in DCM and washed with water (×2) and brine,then dried and concentrated. The crude product was purified by columnchromatography. Elution with EtOAc/pentane yielded the title compound asa yellow gum which crystallised on standing (2.11 g). δ_(H) (CDCl₃, 400MHz) 8.03 (1H, dd), 7.91 (1H, dd), 7.70 (1H, m), 4.22 (1H, br.s), 3.84(1H, d), 3.61 (2H, m), 3.12 (1H, td), 2.74 (1H, m), 2.57 (1H, m), 2.27(1H, dd), 2.11 (1H, m), 1.46 (9H, s), 1.25 (3H, d). MS (ES): MH⁺ 354.1.

Description 66 1,1-Dimethylethyl(2S)-4-[(4-amino-2-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D66)

1,1-Dimethylethyl(2S)-4-[(2-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D65) (2.05 g, 5.801 mmol) was taken up in methanol (50 mL) and wet (50%w/w water) 5% platinum on carbon (2 g) and triethylamine (8 mL, 58.01mmol) were added. The mixture was hydrogenated at atmospheric pressureand room temperature for 2.5-3 h. The mixture was filtered and thefiltrate concentrated to give the crude product which was purified bycolumn chromatography. Elution with EtOAc/pentane yielded the titlecompound as an almost colourless gum (1.15 g). δ_(H) (CDCl₃, 400 MHz)7.11 (1H, t), 6.42 (1H, dd), 6.35 (1H, dd), 4.17 (1H, br.s), 3.79 (1H,d), 3.72 (2H, s), 3.43 (2H, m), 3.07 (1H, td), 2.74 (1H, m), 2.58 (1H,d), 2.14 (1H, dd), 1.99 (1H, m), 1.45 (9H, s), 1.20 (3H, d).

Description 67 1,1-Dimethylethyl(2S)-4-{[2-fluoro-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D67)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-[(4-amino-2-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D66) using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. overnight prior to additionof sodium borohydride and for 24 h after addition. δ_(H) (CDCl₃, 400MHz) 7.11 (1H, t), 6.35 (1H, dd), 6.27 (1H, dd), 4.17 (1H, br.s), 3.78(2H, m), 3.44 (2H, m), 3.07 (1H, td), 2.82 (3H, s), 2.75 (1H, m), 2.59(1H, m), 2.14 (1H, dd), 1.99 (1H, m), 1.44 (9H, s), 1.21 (3H, d).

Description 68 1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate(D68)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-{[2-fluoro-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D64) using a method similar to that described for D54 in Description 54although no aqueous work-up was carried out. The reaction mixture wasconcentrated and used directly in the next step. MS (ES): MH⁺ 477.11.

Description 69 1,1-Dimethylethyl(2S)-4-({3-fluoro-4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D69)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate(D68) and 4-fluorophenol using a method similar to that described forD55 in Description 55 although only 1 eq of 4-fluorophenol was addedinitially, the reaction was heated at 130° C. over-weekend, further4-fluorophenol (2 eq) and potassium carbonate (4 eq) were added and thereaction was heated at 130° C. overnight. The product was purified bycolumn chromatography. δ_(H) (CDCl₃, 400 MHz) 8.07 (1H, s), 7.73 (1H,dd), 7.04 (7H, m), 6.74 (1H, d), 4.19 (1H, br.s), 3.80 (1H, d), 3.43(4H, m), 3.33 (1H, d), 3.08 (1H, td), 2.67 (1H, d), 2.49 (1H, d), 2.13(1H, dd), 2.00 (1H, m), 1.45 (9H, s), 1.21 (3H, d).

Description 70 1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-2-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate(D70)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-{[2-fluoro-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D67) using a method similar to that described for D54 in Description 54although no aqueous work-up was carried out. The reaction mixture wasconcentrated and used directly in the next step. MS (ES): MH⁺ 477.1.

Description 71 1,1-Dimethylethyl(2S)-4-({2-fluoro-4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D71)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-2-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate(D70) and 4-fluorophenol using a method similar to that described forD55 in Description 55 although the reaction temp./time was 130° C. for 8h and purification was carried out by column chromatography. δ_(H)(CDCl₃, 400 MHz) 8.07 (1H, dd), 7.70 (1H, dd), 7.33 (1H, t), 7.05 (4H,m), 6.78 (3H, m), 4.19 (1H, br.s), 3.81 (1H, d), 3.47 (5H, m), 3.07 (1H,td), 2.71 (1H, d), 2.53 (1H, d), 2.18 (1H, dd), 2.04 (1H, m), 1.46 (9H,s), 1.20 (3H, d).

Description 72 1,1-Dimethylethyl(2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D72)

Step 1: 5-Bromo-2-pyridinecarbonitrile (1 g, 5.464 mmol) was dissolvedin EtOH (20 mL) and water (20 mL) and treated with potassium hydroxide(1.53 g, 27.32 mmol). The reaction mixture was heated to 80° C. for 24h. The solvent was removed under vacuum and the residue was taken up inwater and acidified to pH 4 with 2M HCl. The aqueous layer was extractedwith ethyl acetate (×3) and the combined organic layers dried andconcentrated to give 5-bromo-2-pyridinecarboxylic acid (0.704 g) as anorange solid which was used in step 2.

Step 2: The acid from step 1 (0.702 g, 3.475 mmol) was suspended in DCM(40 mL) under argon, DMF (1 drop) was added and the mixture was cooledin an ice-bath. Oxalyl chloride was added portion-wise over 5 minutesand the mixture was then heated to 40° C. for 90 minutes. On cooling,the solvent was removed to produce 5-bromo-2-pyridinecarbonyl chloride(0.801 g) as a brown solid which was used in step 3.

Step 3: The acid chloride from step 2 (0.801 g, 3.633 mmol) in DCM (10mL) was added to a solution of 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.928 g, 2.906 mmol) in DCM (20 mL). Triethylamine (1.009 mL,7.266 mmol) was added and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM and washed withwater. The aqueous layer was re-extracted with DCM (×2) and the combinedorganics were dried and concentrated to give the crude product which waspurified by column chromatography. Elution with a 0-50% ethylacetate/petroleum ether gradient yielded the title compound as a yellowoil (1.432 g). δ_(H) (CDCl₃, 400 MHz) 8.34 (1H, br.s), 7.72 (1H, br.d),7.38 (1H, br.d), 7.18 (2H, br.m), 6.98 (2H, br.s), 4.17 (1H, br.s), 3.79(1H, d), 3.51 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, td), 2.68(1H, d), 2.47 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.45 (9H, s), 1.19(3H, d). MS (ES): MH⁺ 503/505.

Description 73 1,1-Dimethylethyl(2S)-4-({4-[({5-[(4-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D73)

1,1-Dimethylethyl(2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D72) (0.2 g, 0.397 mmol), 4-fluorophenol (0.089 g, 0.794 mmol), cesiumcarbonate (0.259 g, 0.794 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione(TMHD) (0.008 g, 0.040 mmol) were combined in NMP (3 mL) under argon.Copper (I) chloride (0.02 g, 0.199 mmol) was added and the mixtureheated at 120° C. overnight. A second portion of 4-fluorophenol, copper(I) chloride, cesium carbonate and TMHD was added and heating continuedat 120° C. overnight. After cooling to room temperature, the mixture waspartially concentrated, the residue was taken up in EtOAc and washedwith saturated aqueous NaHCO₃ and water. The organic layer was dried andconcentrated to give the crude product which was purified by columnchromatography. Elution with 0-50% ethyl acetate/petroleum ether yieldedthe title compound as a yellow oil (0.161 g). δ_(H) (CDCl₃, 400 MHz)8.04 (1H, br.s), 7.49 (1H, br.d), 7.20 (2H, d), 7.00 (7H, m), 4.17 (1H,br.s), 3.79 (1H, d), 3.51 (3H, s), 3.47 (1H, d), 3.33 (1H, d), 3.08 (1H,td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.99 (1H, m), 1.46 (9H,s), 1.19 (3H, d). MS (ES): MH⁺ 535.4.

Description 74 1,1-Dimethylethyl(2S)-4-({4-[({5-[(3-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D74)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D72) and 3-fluorophenol using a method similar to that described forD73 in Description 73 although 1 eq. CuCl and 0.25 eq. THMD were used.MS (ES): MH⁺ 535.3.

Description 75 1,1-Dimethylethyl(2S)-4-({4-[({5-[(3-cyanophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D75)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D72) and 3-cyanophenol using a method similar to that described for D73in Description 73 although the reaction was worked up after the firstnight of heating. MS (ES): MH⁺ 542.3.

Description 76 1,1-Dimethylethyl(2S)-4-({4-[({5-[(4-fluorophenyl)amino]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D76)

The title compound was prepared 1,1-dimethylethyl(2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D72) and 4-fluoroaniline using a method similar to that described forD58 in Description 58 although the reaction time was 18 h. MS (ES): MH⁺534.2.

Description 77 N-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D77)

4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended inTHF (50 mL) and borane-THF complex (1 M in THF, 26 mL, 26 mmol) addeddrop-wise over ˜15 minutes. The reaction mixture was stirred under argonat room temperature overnight then quenched with water (52 mL) andextracted with ethyl acetate (×3). The combined organics were dried andconcentrated to give the crude product which was purified by columnchromatography. Elution with 0-100% ethyl acetate/petroleum etheryielded the title compound as a cream solid (0.379 g). δ_(H) (MeOD, 400MHz) 7.36 (2H, m), 7.25 (1H, d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H,s). MS (ES): MH⁺ 180.2.

Description 78 N-(4-Formyl-3-methylphenyl)acetamide (D78)

N-[4-(Hydroxymethyl)-3-methylphenyl]acetamide (D77) (0.36 g, 2 mmol) andmanganese dioxide (0.875 g, 10 mmol) were combined in acetonitrile (16mL) and heated to 120° C. in the microwave for 7 minutes. The MnO₂ wasfiltered off and the reaction mixture was concentrated to give the crudeproduct which was purified by column chromatography. Elution with 0-100%ethyl acetate/petroleum ether yielded the title compound as a creamsolid (0.326 g). δ_(H) (CDCl₃, 400 MHz) 10.17 (1H, s), 7.77 (1H, d),7.51 (1H, d), 7.45 (1H, s), 7.36 (1H, br.s), 2.66 (3H, s), 2.22 (3H, s).MS (ES): MH⁺ 178.2.

Description 79 1,1-Dimethylethyl(2S)-4-{[4-(acetylamino)-2-methylphenyl]methyl}-2-methyl-1-piperazinecarboxylate(D79)

N-(4-Formyl-3-methylphenyl)acetamide (D78) (326 mg, 1.8 mmol),1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride(436 mg, 1.8 mmol), triethylamine (0.282 mL, 2 mmol) and sodiumtri(acetoxy)borohydride (781 mg, 3.7 mmol) were stirred together in DCE(15 mL) for 17 h. Saturated aqueous NaHCO₃ (15 mL) was added and thereaction mixture stirred for 1 h. The organic layer was separated andwashed with water and brine, then dried and concentrated to give thecrude product which was purified by chromatography. Elution with 0-100%ethyl acetate/petroleum ether yielded the title compound as a colourlessoil (573 mg). δ_(H) (CDCl₃, 400 MHz) 7.27 (2H, m), 7.16 (1H, d), 7.11(1H, br.s), 4.17 (1H, m), 3.78 (1H, m), 3.36 (2H, s), 3.02 (1H, m), 2.70(1H, m), 2.56 (1H, m), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45(9H, s), 1.18 (3H, d). MS (ES): MH⁺ 362.3.

Description 80 1,1-Dimethylethyl(2S)-4-[(4-amino-2-methylphenyl)methyl]-2-methyl-1-piperazinecarboxylate(D80)

1,1-Dimethylethyl(2S)-4-{[4-(acetylamino)-2-methylphenyl]methyl}-2-methyl-1-piperazinecarboxylate(D79) (497 mg, 1.4 mmol) in KOH (1 M aq soln., 5 mL) and methanol (5 mL)was heated to 140° C. for 1 h in a microwave reactor. The reactionmixture was diluted with methanol (5 mL) and heated for a total of 4 h55 minutes at 130° C. in the microwave. The reaction mixture wasconcentrated to remove the methanol and partitioned between DCM andwater. The organic layer was dried and concentrated to give the crudeproduct which was purified by chromatography. Elution with 0-100%diethyl ether/petroleum ether followed by a column flush with 10% (2MNH₃ in methanol) in DCM yielded the title compound as a yellow oil (223mg). δ_(H) (CDCl₃, 400 MHz) 6.97 (1H, d), 6.52 (1H, d), 6.46 (1H, dd),4.17 (1H, br.s), 3.76 (1H, d), 3.57 (2H, br.s), 3.29 (2H, m), 3.01 (1H,td), 2.70 (1H, d), 2.56 (1H, d), 2.30 (3H, s), 2.10 (1H, dd), 1.90 (1H,m), 1.45 (9H, s), 1.18 (3H, d). MS (AP⁺): MNa⁺ 342.3 (MNa⁺), nomolecular ion (MH⁺) observed.

Description 81 1,1-Dimethylethyl(2S)-2-methyl-4-{[2-methyl-4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D81)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-[(4-amino-2-methylphenyl)methyl]-2-methyl-1-piperazinecarboxylate(D80) using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. for 16 h prior to addition ofsodium borohydride and 5.5 h after addition. δ_(H) (CDCl₃, 400 MHz) 7.00(1H, d), 6.45 (1H, d), 6.39 (1H, dd), 4.17 (1H, br.s), 3.76 (1H, d),3.57 (1H, br.s), 3.33 (1H, d), 3.27 (1H, d), 3.01 (1H, td), 2.82 (3H,s), 2.71 (1H, d), 2.58 (1H, d), 2.32 (3H, s), 2.11 (1H, dd), 1.90 (1H,m), 1.45 (9H, s), 1.17 (3H, d). MS (AP⁺): 356.2 (MNa⁺), 234.2, nomolecular ion (MH⁺) observed.

Description 81: Alternative Method (A) 1,1-Dimethylethyl(2S)-4-{[2-methyl-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D81)

To a mixture of 2-methyl-4-(methylamino)benzaldehyde (D93) (0.397 g) and1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.533 g, 2.66mmol) in 1,2-DCE (35 mL) was added sodium tri(acetoxy)borohydride (0.847g, 4.00 mmol) and the reaction stirred at room temperature overnight.Saturated aqueous NaHCO₃ (30 mL) was added and the mixture was stirredfor 4 h. The reaction mixture was extracted with DCM and the organicswere dried and concentrated to give the crude product which was purifiedby column chromatography. Elution with ether/petroleum ether gave thetitle compound as a colourless oil (0.328 g).

Description 82 (3R,5S)-1-[(4-Nitrophenyl)methyl]-3,5-dimethylpiperazine(D82)

The title compound was prepared from 4-nitrobenzaldehyde and(2R,6S)-2,6-dimethylpiperazine using a method similar to that describedfor D1 in Description 1A. MS (ES): MH⁺ 250.2

Description 83 1,1-Dimethylethyl methylcarbamate (D83)

To a solution of Boc anhydride (7.5 g, 34.36 mmol) in DCM (40 mL) wasadded methylamine (173 mL, 2M solution in THF, 345 mmol) and thereaction mixture was stirred at room temperature overnight. The solventand excess methylamine were removed in vacuo and dilute 2M HCl (10 mL)was added. The aqueous layer was extracted with DCM (×2) and thecombined organics were dried and concentrated to give the title compoundas a yellow oil (3.791 g). δ_(H) (CDCl₃, 400 MHz) 4.58 (1H, br.s), 2.73(3H, d), 1.44 (9H, s).

Description 84 1,1-Dimethylethyl (6-formyl-3-pyridinyl)methylcarbamate(D84)

A mixture of 5-bromo-2-pyridinecarbaldehyde (1.5 g, 8.064 mmol),1,1-dimethylethyl methylcarbamate (D83) (1.267 g, 9.677 mmol),tris(dibenzylideneacetone) dipalladium(0) (0.148 g, 0.161 mmol),xantphos (0,373 g, 0.645 mmol) and cesium carbonate (3.678 g, 11.289mmol) in dioxane (35 mL) was heated at 110° C. overnight under an argonatmosphere. On cooling, the solvent was removed in vacuo and the residuepartitioned between EtOAc and water. The organic layer was separated,washed with water and brine, dried and concentrated to give the crudeproduct which was purified by column chromatography. Elution with 0-50%ether/petroleum ether gave the title compound as a brown oil (0.977 g).δ_(H) (CDCl₃, 400 MHz) 10.01 (1H, s), 8.79 (1H, d), 7.94 (1H, d), 7.86(1H, dd), 3.40 (3H, s), 1.53 (9H, s). MS (ES⁺): 259.1 (MNa⁺), 181.2, nomolecular ion (MH⁺) observed.

Description 85 5-(Methylamino)-2-pyridinecarbaldehyde and6-[bis(methyloxy)methyl]-N-methyl-3-pyridinamine (D85)

To a solution of 1,1-dimethylethyl (6-formyl-3-pyridinyl)methylcarbamate(D84) (0.977 g, 4.139 mmol) in DCM (80 mL) was added TFA (20 mL) and thereaction mixture was stirred at room temperature for 2 h. The solventwas removed in vacuo and the residue was taken up in methanol and elutedthrough an SCX (10 g) column with methanol then 2M NH₃ in methanolsolution. The ammoniacal fraction was concentrated to give a yellow oil(0.622 g) which was an approximately 1:1 mixture of the title compounds.This material was used directly in the next step. MS (ES⁺): aldehyde-137(MH⁺); acetal-151. MS (AP⁺): aldehyde-137 (MH⁺); acetal-205 (MNa⁺), 151.

Description 86 1,1-Dimethylethyl(2S)-2-methyl-4-{[5-(methylamino)-2-pyridinyl]methyl}-1-piperazinecarboxylate(D86)

A mixture of 5-(methylamino)-2-pyridinecarbaldehyde and6-[bis(methyloxy)methyl]-N-methyl-3-pyridinamine (D85) (0.622 g),1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.910 g, 4.552mmol) and triethylamine (0.418 g, 4.139 mmol) in 1,2-DCE (40 mL) wasstirred at room temperature overnight. Sodium tri(acetoxy)borohydride(1.14 g, 5.38 mmol) was added and the reaction stirred at roomtemperature overnight. The reaction mixture was diluted with DCM andwashed with saturated aq. NaHCO₃ solution and water. The organic layerwas dried and concentrated to give the crude product which was purifiedby column chromatography. Elution with 0-100% EtOAc/petroleum ether gavethe title compound as a yellow/brown oil (0.542 g). δ_(H) (CDCl₃, 400MHz) 7.96 (1H, d), 7.23 (1H, d), 6.88 (1H, dd), 4.17 (1H, br.s), 3.80(2H, d), 3.58 (1H, d), 3.45 (1H, d), 3.12 (1H, td), 2.86 (3H, s), 2.76(1H, m), 2.58 (1H, m), 2.18 (1H, dd), 2.07 (1H, m), 1.45 (9H, s), 1.23(3H, d). MS (ES): MH⁼321.4

Description 87 1,1-Dimethylethyl(2S)-2-methyl-4-({4-[(1-methylethyl)amino]phenyl}methyl)-1-piperazinecarboxylate(D87)

To a stirred solution of 1,1-dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(0.30 g, 1 mmol) in dry 1,2 DCE (5 mL) was added sequentially2-methoxypropene (0.141 mL, 1.5 mmol), acetic acid (0.056 mL, 1 mmol)and sodium triacetoxyborohydride (0.313 g, 1.5 mmol). Further 1,2 DCE (5mL) was added and the reaction mixture was stirred under argon at roomtemperature for 16 hours. Saturated NaHCO₃ (15 mL) was added andreaction mixture stirred for a further 1 hour. The aqueous layer wasthen extracted with DCM (×3) and the combined organic layers were dried(Na₂SO₄) and concentrated in vacuo. The crude material was purified bycolumn chromatography eluting with 0-100% ether/petroleum ether to givethe title compound (0.265 g). δ_(H) (CDCl₃, 400 MHz) 7.09 (2H, d), 6.54(2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.61 (1H, sp), 3.49 (1H, s),3.42 (2H, m), 3.28 (1H, d), 3.08 (1H, td), 2.75 (1H, d), 2.59 (1H, d),1.95 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.20 (9H, m). MS (AP⁺): 370.3(MNa⁺), 248.3, no molecular ion (MH⁺) observed.

Description 88 1,1-Dimethylethyl(2S)-4-{[4-(ethylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D88)

1,1-dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(0.30 g, 1 mmol), acetaldehyde (0.055 mL, 1 mmol), sodiumtriacetoxyborohydride (0.417 g, 2 mmol) and triethylamine (0.151 mL, 1.1mmol) were combined in dry 1,2-DCE (15 mL) and stirred under Ar at roomtemperature for 48 hours. Saturated NaHCO₃ (15 mL) was added andreaction mixture stirred for a further 2 hours. The aqueous layer wasthen extracted with DCM (×3) and the combined organic layers were dried(Na₂SO₄) and concentrated in vacuo. The crude material was purified bycolumn chromatography eluting with 0-100% ether/petroleum ether to givethe title compound (0.239 g). δ_(H) (CDCl₃, 400 MHz) 7.11

(2H, d), 6.56 (2H, dd), 4.16 (1H, br.s), 3.78 (1H, d), 3.51 (1H, br.s),3.42 (1H, d), 3.29 (1H, d), 3.15 (2H, q), 3.08 (1H, td), 2.75 (1H, d),2.59 (1H, d), 2.06 (1H, dd), 1.93 (1H, m), 1.45 (9H, s), 1.25 (3H, t),1.21 (3H, d). MS (ES⁺): 234.2, no molecular ion (MH⁺) observed.

Description 89 (Methyloxy)acetaldehyde (D89)

To a stirred suspension of chromatographic grade silica gel (3.8 g) indry DCM (25 mL) was added NalO4 (3.8 mL, 0.65M aq. solution) dropwise. Asolution of 3-(methyloxy)-1,2-propanediol (200 mg, 1.9 mmol) in 1,2-DCEwas added and reaction mixture was stirred at room temperature. After 2hours, tlc showed complete reaction so the reaction mixture was filteredand the filter cake was washed with further 1,2-DCE. The filtratecontaining the title compound was used directly in the next step (D90)

Description 90 1,1-Dimethylethyl(2S)-2-methyl-4-[(4-{[2-(methyloxy)ethyl]amino}phenyl)methyl]-1-piperazinecarboxylate(D90)

A mixture of 1,1-dimethylethyl(2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2)(0.30 g, 1 mmol), (methyloxy)acetaldehyde (D89), sodiumtri(acetoxy)borohydride (0.417 g, 2 mmol) and triethylamine (0.165 mL,1.2 mmol) in 1,2-DCE (15 mL) was stirred under Ar at room temperaturefor 19 hours. Saturated NaHCO₃ (20 mL) was added and reaction mixturestirred for a further 1 hour. The reaction mixture was further dilutedwith DCM (25 mL) and water (10 mL). The aqueous layer was then extractedwith DCM (×3) and the combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The crude material was purified by columnchromatography on silica eluting with 0-50% EtOAc/petroleum ether togive the title compound (0.310 g). δ_(H) (CDCl₃, 400 MHz) 7.12 (2H, d),6.59 (2H, d), 4.15 (1H, m), 3.99 (1H, br.s), 3.78 (1H, d), 3.61 (2H, t),3.40 (3H, s), 3.28 (3H, m), 3.08 (1H, td), 2.74 (1H, d), 2.58 (1H, d),2.06 (1H, m), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d). MS (ES⁺): 264.2,no molecular ion (MH⁺) observed.

Description 91 4-Bromo-2-methylbenzaldehyde (D91)

To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL)cooled to 5 C under argon was added Dibal-H (11.2 mL, 1 M solution intoluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30minutes then MeOH (3 mL) and 2 M H₂SO₄ (10 mL) were added dropwise. Themixture was stirred for ˜19 h then concentrated in vacuo. The residuewas re-dissolved in water/EtOAc. The organic layer was dried andconcentrated to give the crude title compound as a brown oil (1.81 g)which was used in the next step without further purification. δ_(H)(CDCl₃, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H,m), 2.64 (3H, s).

Description 92 1,1-Dimethylethyl(4-formyl-3-methylphenyl)methylcarbamate (D93)

The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde(D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similarto that described for D84 in Description 84. δ_(H) (CDCl₃, 400 MHz)10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s),2.66 (3H, s), 1.49 (9H, s).

Description 93 2-Methyl-4-(methylamino)benzaldehyde (D93)

To 1,1-dimethylethyl (4-formyl-3-methylphenyl)methylcarbamate (D92)(0.614 g, 2.47 mmol) in DCM (60 mL) at room temperature under argon wasadded TFA (15 mL) dropwise. The mixture was stirred for 0.5 h thenconcentrated. The residue was re-dissolved in DCM and water and theaqueous layer was basified with NaOH solution. The DCM layer wasseparated, dried (Na₂SO₄) and concentrated to give the crude titlecompound as a yellow oil (0.397 g) which was used in the next stepwithout further purification. δ_(H) (CDCl₃, 400 MHz) 9.98 (1H, s), 7.63(1H, d), 6.47 (1H, dd), 6.35 (1H, d), 4.35 (1H, br.s), 2.91 (3H, d),2.60 (3H, s). MS (ES): MH⁺ 150.1.

Description 94 6-(Methylamino)-3-pyridinecarbonitrile (D94)

Four batches of 6-chloro-3-pyridinecarbonitrile (0.40 g, 2.89 mmol) inmethylamine (16 mL, 2M solution in THF) were each heated at 80° C. for30 minutes in a microwave reactor. The reaction mixtures were combinedand concentrated in vacuo. The residue was re-dissolved in EtOAc/waterand the organic layer was separated, dried (Na₂SO₄) and concentrated.The crude product was purified by column chromatography; elution withEtOAc/petroleum ether gave the title compound as a white solid (1.46 g).δ_(H) (CDCl₃, 400 MHz) 8.37 (1H, d), 7.59 (1H, dd), 6.39 (1H, dd), 5.19(1H, br.s), 2.99 (3H, d). MS (ES): MH⁺ 134.2.

Description 95 6-(Methylamino)-3-pyridinecarbaldehyde (D95)

To 6-(methylamino)-3-pyridinecarbonitrile (D94) (0.1 g, 0.752 mmol) intoluene (10 mL) cooled to −78 C under argon was added Dibal-H (1.88 mL,1 M solution in toluene, 11.2 mmol) dropwise. The reaction was stirredat −78° C. and then allowed to warm to room temperature overnight. MeOH(0.47 mL) and 2 M H₂SO₄ (1.42 mL) were added and mixture was stirred for1.5 h then concentrated in vacuo. The residue was partitioned betweenwater and EtOAc. The aqueous layer was extracted with EtOAc and thecombined organic layers were dried and concentrated to give the titlecompound (0.067 g). δ_(H) (CDCl₃, 400 MHz) 9.78 (1H, s), 8.52 (1H, d),7.92 (1H, dd), 6.45 (1H, d), 5.38 (1H, br.s), 3.04 (3H, d). MS (ES): MH⁺137.1.

Description 96 1,1-Dimethylethyl(2S)-2-methyl-4-{[6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate(D96)

The title compound was prepared from6-(methylamino)-3-pyridinecarbaldehyde (D95) and 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate using a method similar to thatdescribed for D81 in Description D81 A. δ_(H) (CDCl₃, 400 MHz) 7.97 (1H,d), 7.44 (1H, dd), 6.38 (1H, d), 4.51 (1H, m), 4.17 (1H, br.s), 3.79(1H, d), 3.38 (1H, d), 3.26 (1H, d), 3.07 (1H, td), 2.92 (3H, d), 2.74(1H, m), 2.57 (1H, m), 2.09 (1H, dd), 1.96 (1H, m), 1.45 (9H, s), 1.20(3H, d). MS (ES⁺): 343.2 (MNa⁺), 265.2, no molecular ion (MH⁺) observed.

Description 97 6-Amino-4-methyl-3-pyridinecarbonitrile (D97)

A mixture of 5-bromo-4-methyl-2-pyridinamine (0.50 g, 2.7 mmol) andcopper (I) cyanide (0.263 g, 2.9 mmol) in DMF (12 mL) was heated at 200°C. for a total of 1.75 h in a microwave reactor. The reaction mixturewas diluted with EtOAc and water. The resulting thick dark precipitatewas filtered off. The filtrate was extracted with EtOAc (×3) and thecombined extracts were dried and concentrated to give a dark yellowsolid (0.115 g). The filter cake was and washed with 1:1 DCM/MeOH (1 L)which was concentrated to give a second batch of dark yellow solid(0.047 g). The filter cake was washed with 2M NH₃ in MeOH (200 mL) whichwas concentrated to give a dark green solid (0.533 g). These 3 batchesof solids were purified by column chromatography using 0-100%EtOAc/hexane as the eluent to give the title compound as a white solid(total yield: 0.213 g). δ_(H) (CDCl₃, 400 MHz) 8.28 (1H, s), 6.36 (1H,s), 4.87 (2H, br.s), 2.40 (3H, s). MS (ES): MH⁺ 134.1.

Description 98 N-(5-Cyano-4-methyl-2-pyridinyl)-2,2,2-trifluoroacetamide(D98)

To a solution of 6-amino-4-methyl-3-pyridinecarbonitrile (D97) (0.213 g,1.6 mmol) and 2,6-lutidine (0.37 mL, 3.2 mmol) in DCM (20 mL) cooled to0° C. under argon was added trifluoroacetic anhydride (0.22 mL, 1.6mmol) as a solution in DCM. The reaction mixture was stirred for 17 h,gradually warming to room temperature. The reaction mixture wasre-cooled to 0° C. and further 2,6-lutidine (0.37 mL) andtrifluoroacetic anhydride (0.22 mL) were added. The reaction was stirredat room temperature for 4 h then diluted with 10% citric acid solutionand extracted with DCM. The DCM layer was washed with brine, dried andconcentrated to give the crude product which was purified by columnchromatography. Elution with 0-100% EtOAc/hexane gave the title compoundas a white solid (0.299 g). δ_(H) (CDCl₃, 400 MHz) 8.68 (1H, br.s), 8.55(1H, s), 8.21 (1H, s), 2.62 (3H, s).

Description 99 6-Amino-4-methyl-3-pyridinecarbaldehyde (D99)

A solution of N-(5-cyano-4-methyl-2-pyridinyl)-2,2,2-trifluoroacetamide(D98) (0.050 g, 0.22 mmol) in formic acid (1.35 mL) was diluted withwater (0.48 mL) and nickel/aluminium alloy (0.122 g) was added. Thereaction mixture was heated at reflux under argon for 2 h then filteredwhile still hot, washing with further formic acid (3×5 mL). The filtrateand washings were concentrated, diluted with toluene (5 mL) andre-concentrated to give the crude title compound as a pale yellow solid(0.053 g) which was used in the next step without further purification.δ_(H) (CDCl₃, 400 MHz) 9.91 (1H, s), 8.34 (1H, s), 6.31 (1H, s), 5.49(2H, br.s), 2.57 (3H, s). MS (ES): MH⁺ 137.2.

Description 100 1,1-Dimethylethyl(2S)-4-[(6-amino-4-methyl-3-pyridinyl)methyl]-2-methyl-1-piperazinecarboxylate(D100)

A mixture of 6-amino-4-methyl-3-pyridinecarbaldehyde (D99) (0.053 g,0.39 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate(0.117 g, 0.58 mmol) and sodium tri(acetoxy)borohydride (0.206 g, 0.97mmol) in 1,2-DCE (10 mL) was sonicated to aid dissolution of thestarting material then stirred at room temperature overnight. Saturatedaqueous NaHCO₃ (30 mL) was added and the mixture was stirred for 24 h.The reaction mixture was extracted with DCM (3×10 mL) and the organicswere dried and concentrated to give the crude title compound as an oil(0.067 g) which was used in the next step without further purification.MS (ES): MH⁺ 321.3, MNa⁺ 343.3.

Description 101 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-methyl-6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate(D101)

To 1,1-dimethylethyl(2S)-4-[(6-amino-4-methyl-3-pyridinyl)methyl]-2-methyl-1-piperazinecarboxylate(D100) (0.067 g, 0.21 mmol) in dry MeOH (4 mL) under an argon atmospherewas added paraformaldehyde (0.019 g, 0.63 mmol) and sodium methoxide(0.057 g, 1.00 mmol). The mixture was stirred at 50° C. overnight thensodium borohydride (0.024 g, 0.63 mmol) was added and the reactionstirred at 50° C. for 24 h. The reaction mixture was concentrated invacuo. The residue was partitioned between DCM and saturated aqueousNaHCO₃ and stirred for 0.5 h. The aqueous phase was extracted with DCM(3×5 mL) and the combined organics were dried and concentrated to give acrude colourless oil. Column chromatography eluting with 0-10% MeOH/DCMgave the crude title compound as a colourless oil (0.037 g) which wasused in the next step without further purification. MS (ES): MH⁺ 335.3.

Description 102 1-(Bromomethyl)-2-chloro-4-nitrobenzene (D102)

A mixture of 2-chloro-4-nitrotoluene (0.20 g, 1.17 mmol),N-bromosuccinimide (0.228 g, 1.28 mmol) and benzoyl peroxide (0.014 g,0.058 mmol) in tetrachloromethane (7 mL) was irradiated (500 W lamp) atreflux overnight. The reaction mixture was concentrated to give a yellowoil/solid (0.391 g) which was used directly in the next step withoutfurther purification.

Description 103 1,1-Dimethylethyl(2S)-4-[(2-chloro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D103)

A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylatehydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes.The reaction mixture was concentrated to give an orange oil which wasdissolved in DCM and washed with water (×2) and brine, then dried andconcentrated to give an orange oil. Purification by columnchromatography eluting with 0-30% EtOAc/pentane gave the title compoundas a yellow oil (0.199 g). δ_(H) (CDCl₃, 400 MHz) 8.24 (1H, d), 8.12(1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s),3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m),1.47 (9H, s), 1.28 (3H, d). MS (ES): MH⁺ 370/372,

Description 104 1,1-Dimethylethyl(2S)-4-[(4-amino-2-chlorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D104)

A mixture of 1,1-dimethylethyl(2S)-4-[(2-chloro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D103) (0.199 g, 0.538 mmol), triethylamine (0.75 mL, 5.38 mmol) and 5%Pt/C catalyst (0.134 g) in MeOH (5 mL) was hydrogenated at roomtemperature and atmospheric pressure for 3 h. The catalyst was removedby filtration and the filtrate was concentrated to give a colourless oilwhich was dissolved in DCM. The DCM solution was washed with water (×2)and brine, then dried and concentrated to give the crude product.Purification by column chromatography eluting with 10-40% EtOAc/pentanegave the title compound as a colourless oil (0.125 g). δ_(H) (CDCl₃, 400MHz) 7.19 (1H, d), 6.69 (1H, d), 6.54 (1H, dd), 4.18 (1H, br.s), 3.79(1H, d), 3.70 (2H, br.s), 3.45 (2H, m), 3.07 (1H, td), 2.74 (1H, m),2.60 (1H, m), 2.19 (1H, dd), 2.03 (1H, m), 1.45 (9H, s), 1.22 (3H, d).MS (ES): MH⁺ 340/342.

Description 105 1,1-Dimethylethyl(2S)-4-{[2-chloro-4-(methylamino)phenyl]methyl}-2-methyl-1-piperazinecarboxylate(D105)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-[(4-amino-2-chlorophenyl)methyl]-2-methyl-1-piperazinecarboxylate(D104) using a method similar to that described for D3 in Description 3Aalthough the reaction was heated at 50° C. overnight prior to, and for24 h after addition of sodium borohydride.(3 eq.). MS (ES): MH⁺ 354/356.

Description 106 1,1-Dimethylethyl(2S)-4-({6-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate(D106)

To 1,1-dimethylethyl(2S)-2-methyl-4-{[6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate(D96) (0.150 g, 0.469 mmol) and triethylamine (0.098 mL, 0.703 mmol) inDCM (7 mL) under argon was added 6-chloro-3-pyridinecarbonyl chloride(0.099 g, 0.562 mmol). The mixture was stirred at room temperature for0.3 h then diluted with DCM and water. The organic layer was dried andconcentrated to give the crude product which was purified by columnchromatography. Elution with EtOAc/DCM gave the title compound as awhite colourless gum (0.139 g). δ_(H) (CDCl₃, 400 MHz) 8.33 (1H, d),8.19 (1H, d), 7.70 (1H, dd), 7.57 (1H, dd), 7.23 (1H, d), 6.86 (1H, d),4.20 (1H, br.s), 3.82 (1H, d), 3.58 (3H, s), 3.49 (1H, d), 3.37 (1H, d),3.08 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.16 (1H, dd), 2.04 (1H, m),1.46 (9H, s), 1.19 (3H, d). MS (ES): MH⁺ 460/462

Description 107 1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D107)

Step 1: 6-bromo-2-pyridinecarboxylic acid (0.348 g, 1.72 mmol) wasdissolved in dry dioxane (15 mL) and thionyl chloride (0.570 mL, 7.84mmol) was added. The reaction mixture was stirred at reflux for 3 h thenconcentrated in vacuo, re-dissolved in dioxane (15 mL) andre-concentrated to give 6-chloro-2-pyridinecarbonyl chloride as a paleyellow solid which was used directly in step 2.

Step 2: The acid chloride from step 1 was dissolved in DCM (15 mL) andadded to a mixture of 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.500 g, 1.57 mmol) and triethylamine (0.284 mL, 2.04 mmol) in DCM(15 mL). The reaction mixture was stirred at room temperature overnightand then washed with water (×2) and brine. The organic layer was driedand concentrated to give the crude product, which was purified by columnchromatography. Elution with 20-60% EtOAc/pentane yielded the titlecompound as a yellow oil/solid (0.658 g). δ_(H) (CDCl₃, 400 MHz) 7.56(1H, m), 7.46 (1H, m), 7.17 (2H, m), 6.99 (2H, m), 4.16 (1H, br.s), 3.79(1H, d), 3.50 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, m), 2.69(1H, d), 2.50 (1H, d), 2.08 (1H, m), 1.97 (1H, m), 1.46 (9H, s), 1.19(3H, d). MS (ES): MH⁺ 459/461.

Description 108 1,1-Dimethylethyl(2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D108)

To 1-hydroxybenzotriazole (0.967 g, 7.16 mmol) andN-benzyl-N′-cyclohexylcarbodiimide resin (4.48 g, 1.6 mmol/g, 7.16 mmol)in DMF (15 mL) was added 6-bromo-3-pyridinecarboxylic acid (0.964 g,4.77 mmol) in DMF (15 mL). The mixture was stirred for 30 minutes underan argon atmosphere and 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (1.52 g, 4.77 mmol) in DCM (15 mL) was added. The mixture wasstirred for 65 h at room temperature. PS-trisamine resin (2 eq. relativeto acid), PS-isocyanate resin (2 eq. relative to amine) and MP-carbonateresin (5 eq. relative to HOBt) were added and the mixture stirred for 4h at room temperature. The mixture was filtered to remove the resinswhich were then washed with further DCM. The filtrate was concentratedto give the crude product which was purified by column chromatography.Elution with an EtOAc/petroleum ether gradient yielded the titlecompound as a white solid (1.43 g). δ_(H) (CDCl₃, 400 MHz) 8.18 (1H, d),7.51 (1H, dd), 7.32 (1H, d), 7.25 (2H, d), 6.98 (2H, d), 4.18 (1H,br.s), 3.80 (1H, d), 3.49 (3H, s), 3.47 (1H, d), 3.34 (1H, d), 3.08 (1H,td), 2.69 (1H, d), 2.49 (1H, d), 2.11 (1H, dd), 1.98 (1H, m), 1.46 (9H,s), 1.20 (3H, d). MS (ES): MH⁺ 503/505.

Tabulated compounds D109-D110 were prepared using methods similar tothose described in Description 15 using the appropriate anilineprecursor and appropriate carboxylic acid.

Aniline Description Precursor Structure D109 D86

D110 D86

Method Comment Description Name Step 1 Step 2 MH+ D109 1,1-dimethylethyl(2S)-4-({5-[({6- Similar method to D15 Similar method to D15 536.3[(4-fluorophenyl)oxy]-3- although sat. aq. pyridinyl}carbonyl)(methyl)NaHCO₃ used in place amino]-2-pyridinyl}methyl)-2- of water in work-upmethyl-1-piperazinecarboxylate D110 1,1-dimethylethyl (2S)-4-({5-[{[6-Similar method to D15 Similar method to D15 520.3 (4-fluorophenyl)-3-although sat. aq. pyridinyl]carbonyl}(methyl) NaHCO₃ used in placeamino]-2-pyridinyl}methyl)-2- of water in work-upmethyl-1-piperazinecarboxylate

Tabulated compounds D111-D117 were prepared using methods similar tothose described in Description 16 using the appropriate anilineprecursor and appropriate carboxylic acid.

Aniline Description Precursor Structure D111 D3

D112 D3

D113 D87

D114 D88

D115 D90

D116 D81

D117 D96

Method Comment Description Name Step 1 Step 2 MH+ D111 1,1-dimethylethyl(2S)-4-({4-[({1- Similar method to D16 Similar method to D16 546.4[(3-cyanophenyl)methyl]-4- although reactionpiperidinyl}carbonyl)(methyl) temp./time: roomamino]phenyl}methyl)-2-methyl-1- temperature, 0.75 hpiperazinecarboxylate D112 1,1-dimethylethyl (2S)-4-({4-[({1- Similarmethod to D16 Similar method to D16 546.4 [(4-cyanophenyl)methyl]-4-although reaction piperidinyl}carbonyl)(methyl) temp./time: roomamino]phenyl}methyl)-2-methyl-1- temperature, 0.75 hpiperazinecarboxylate D113 1,1-dimethylethyl (2S)-4-({4-[{[6- Similarmethod to D16 Similar method to D16 547.3 (3-fluorophenyl)-3- althoughreaction time: although sat. aq. pyridinyl]carbonyl}(1- 0.75 h NaHCO₃used in place methylethyl)amino]phenyl} of water in work-upmethyl)-2-methyl-1- piperazinecarboxylate D114 1,1-dimethylethyl(2S)-4-{[4- Similar method to D16 Similar method to D16 533.2(ethyl{[6-(3-fluorophenyl)-3- although reaction time: although sat. aq.pyridinyl]carbonyl}amino)phenyl] 1 h NaHCO₃ used in placemethyl}-2-methyl-1- of water in work-up piperazinecarboxylate D1151,1-dimethylethyl (2S)-4-[(4-{{[6- Similar method to D16 Similar methodto D16 563.2 (3-fluorophenyl)-3- although reaction time: although sat.aq. pyridinyl]carbonyl}[2- 0.5 h NaHCO₃ used in place(methyloxy)ethyl]amino}phenyl) of water in work-up methyl]-2-methyl-1-piperazinecarboxylate D116 1,1-dimethylethyl (2S)-4-({4-[({6- Similarmethod to D16 Similar method to D16 549.3 [(4-fluorophenyl)oxy]-3-although reaction time: pyridinyl}carbonyl)(methyl) 0.5 hamino]-2-methylphenyl}methyl)-2- methyl-1-piperazinecarboxylate D1171,1-dimethylethyl (2S)-4-({6-[{[6- Similar method to D16 Similar methodto D16 520.2 (3-fluorophenyl)-3- although reaction time:pyridinyl]carbonyl}(methyl) 1 h amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate

Description 118 1,1-Dimethylethyl(2S)-4-({6-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]-4-methyl-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate(D118)

Step 1: 6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14) (0.032g, 0.14 mmol) was solubilised in dry dioxane (2 mL). Thionyl chloride(0.081 mg, 0.14 mmol) was added drop-wise and the reaction mixtureheated at reflux for 1.25 h. The reaction mixture was concentrated, andthen re-concentrated from DCM to give6-[(4-fluorophenyl)oxy]-3-pyridinecarbonyl chloride which was useddirectly in step 2

Step 2: 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-methyl-6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate(D101) (0.038 g, 0.11 mmol) was dissolved in dry DCM (2 mL).Triethylamine (0.016 g, 0.16 mmol) was added dropwise and after 5minutes a solution of the acid chloride from step 1 in dry DCM (2 mL)was added dropwise. The reaction mixture was then left stirring underargon at room temperature overnight. Saturated aqueous NaHCO₃ (15 mL)was added and the aqueous layer extracted with DCM (3×5 mL). The organicextracts were dried (Na₂SO₄) and the crude product was purified bycolumn chromatography. Elution with a 0-100% EtOAc/petroleum ethergradient gave the title compound as a colourless oil (0.026 g). MS (ES):MH⁺ 550.4

Tabulated compounds D119-D122 were prepared using methods similar tothose described in Description 16 using the appropriate anilineprecursor and appropriate carboxylic acid.

Aniline Description Precursor Structure D119 D90

D120 D105

D121 D88

D122 D3

Method Comment Description Name Step 1 Step 2 MH+ D119 1,1-dimethylethyl(2S)-4-[(4-{({6- Similar method to D16 Similar method to D16 579.5[(4-fluorophenyl)oxy]-3- although reaction time: although reactionpyridinyl}carbonyl)[2- 1 h mixture concentrated(methyloxy)ethyl]amino}phenyl) and purified directly methyl]-2-methyl-1-by column piperazinecarboxylate chromatography D120 1,1-dimethylethyl(2S)-4-({2- Similar method to D16 Similar method to D16 569/571chloro-4-[({6-[(4- although reaction time: although reaction time:fluorophenyl)oxy]-3- 3 h 48 h. Reaction mixturepyridinyl}carbonyl)(methyl)amino] concentrated andphenyl}methyl)-2-methyl-1- purified directly piperazinecarboxylate bycolumn chromatography D121 1,1-dimethylethyl (2S)-4-({4- Similar methodto D16 Similar method to D16 549.4 [ethyl({6-[(4-fluorophenyl)oxy]-3-although reaction time: with column pyridinyl}carbonyl)amino]phenyl} 1.5h chromatography and methyl)-2-methyl-1- MDAP purificationpiperazinecarboxylate D122 1,1-dimethylethyl (2S)-2-methyl- Similarmethod to D16 Similar method to D16 518.24-{[4-(methyl{[6-(3-pyridinyloxy)- although reaction time: althoughreaction 3- 1 h mixture concentrated pyridinyl]carbonyl}amino)phenyl]and purified directly methyl}-1-piperazinecarboxylate by columnchromatography

Description 123 1,1-Dimethylethyl(2S)-2-methyl-4-[(4-{methyl[(4-{[4-(trifluoromethyl)phenyl]carbonyl}phenyl)carbonyl]amino}phenyl)methyl]-1-piperazinecarboxylate(D123)

Step 1: 4-{[4-(Trifluoromethyl)phenyl]carbonyl}benzoic acid (200 mg,0.68 mmol) was stirred in dioxane (5 mL) and thionyl chloride (0.496 mL,6.8 mmol) added. The reaction mixture was heated at reflux for 1 h.Further thionyl chloride (0.496 mL, 6.8 mmol) was added and heatingcontinued for 3 h. On cooling, the reaction mixture was concentrated invacuo to give 4-{[4-(trifluoromethyl)phenyl]carbonyl}benzoyl chloride asan oily white liquid (0.286 g) which was used directly in step 2.

Step 2: The acid chloride from step 1 was taken up in DCM (2 mL) andadded drop-wise to a mixture of 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (0.170 g, 0.53 mmol) and triethylamine (0.11 mL) in DCM (2 mL). Thereaction mixture was stirred at room temperature under argon overnightthen diluted with water (20 mL) and DCM (20 mL). The aqueous layer wasextracted with DCM (20 mL) and the combined organic layers were dried,concentrated and purified by column chromatography. Elution with 0-30%EtOAc/pentane gave the title compound as a colourless oil (0.244 g). MS(ES): MH⁺ 596.2.

Description 124 1,1-Dimethylethyl(2S)-4-({6-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate(D124)

To 1,1-dimethylethyl(2S)-4-({6-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate(D106) (0.139 g, 0.303 mmol) in DMF (4 mL) under an argon atmosphere wasadded potassium carbonate (0.293 g, 0.212 mmol) and 4-fluorophenol(0.169 g, 1.51 mmol). The reaction mixture was stirred and heated at130° C. for 5 h then concentrated in vacuo. The residue was re-dissolvedin DCM/water. The organic layer was washed with 2M NaOH solution andbrine then dried (Na₂SO₄) and concentrated to give the crude productwhich was purified by column chromatography. Elution with EtOAc/DCM gavethe title compound as a colourless oil (0.054 g). MS (ES): MH⁺ 536.2.

Description 125 1,1-Dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D125)

To sodium hydride (0.0174 g, 60% dispersion in mineral oil, 0.436 mmol)in DMF (4 mL) was added 4-fluorophenol (0.0488 g, 0.436 mmol) and themixture stirred under an argon atmosphere for 20 minutes.1,1-Dimethylethyl(2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D107) (0.100 g, 0.218 mmol) was added and the reaction mixture washeated in a microwave at 190° C. for 1.5 h. The reaction mixture wasconcentrated and the residue partitioned between DCM and water. Theaqueous layer was further extracted with DCM and the combined organicswere dried over Na₂SO₄ and concentrated to give a yellow oil which waspurified by column chromatography to give the title compound as acolourless oil (0.0539 g). MS (ES): MH⁺ 535.4.

Description 126 1,1-Dimethylethyl(2S)-4-({4-[({6-[(3-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D126)

The title compound was prepared from 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D107) and 3-fluorophenol using a procedure similar to that describedfor D125 in Description 125 although the reaction time was 3.3 h. MS(ES): MH⁺ 535.4.

Description 127 1,1-Dimethylethyl(2S)-4-({4-[{[6-(4-fluoro-1-piperidinyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D127)

A mixture of 1,1-dimethylethyl(2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D108) (0.050 g, 0.0993 mmol), 4-fluoropiperidine (0.055 g, 0.397 mmol)and triethylamine (0.069 mL, 0.497 mmol) in acetonitrile (4 mL) washeated at 85° C. overnight then in a microwave at 140° C. for 10 h.Further portions of 4-fluoropiperidine (5 eq.) and triethylamine (5 eq.)were added and the reaction heated at 170° C. for 2 h. The reactionmixture was concentrated and the residue dissolved in DCM/water. Theaqueous layer was further extracted with DCM (×3) and the combinedorganics were dried (Na₂SO₄) and concentrated to give the title compoundas a yellow oil (0.0538 g). MS (ES): MH⁺ 526.2.

Description 128 1,1-Dimethylethyl(2S)-4-({4-[{[6-(4,4-difluoro-1-piperidinyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D128)

A mixture of 1,1-dimethylethyl(2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D108) (0.050 g, 0.0993 mmol), 4,4-difluoropiperidine (0.141 g, 0.894mmol) and triethylamine (0.138 mL, 0.993 mmol) in acetonitrile (4 mL)was heated in a microwave at 150° C. for 12 h. Further portions of4,4-difluoropiperidine (4 eq.) and triethylamine (5 eq.) were added andthe reaction heated at 150° C. for 1 h. The reaction mixture wasconcentrated and the residue dissolved in DCM/water. The aqueous layerwas further extracted with DCM (×3) and the combined organics were dried(Na₂SO₄) and concentrated to give a yellow gum which was purified bycolumn chromatography. Elution with 0-100% EtOAc/hexane gave acolourless gum which was a mixture (˜9:1) of the title compound andunreacted D109 (0.0485 g). MS (ES): MH⁺ 544.2.

Description 129 1,1-Dimethylethyl(2S)-4-({4-[{[6-(3-fluorophenyl)-2-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D129)

A mixture of 1,1-dimethylethyl(2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D107) (0.0825 g, 0.179 mmol), 3-fluorobenzeneboronic acid (0.0302 g,0.216 mmol), tetrakis-(triphenylphosphine)palladium (0) (0.0104 g, 0.009mmol) and sodium carbonate (0.0762 g, 0.719 mmol) in a DME/water (4 mL,1:1) was heated at 140° C. in a microwave for 10 minutes. The reactionmixture was diluted with DCM/water and the aqueous layer was furtherextracted with DCM (×3). The combined organics were dried andconcentrated to give the crude product which was purified by columnchromatography. Elution with 0-100% EtOAc/hexane gave the title compoundas a colourless oil (0.0781 g). MS (ES): MH⁺ 519.3.

Tabulated compounds D130-D136 were prepared from the appropriatebromo-pyridine precursor as indicated and the appropriate boronic acidusing methods similar to that described for D129 in Description 129.

Bromo- De- pyridine script- Pre- Method tion cursor Structure NameComment MH⁺ D130 D72

1,1-Dimethylethyl (2S)-2-methyl-4-[(4-{methyl[(2′-methyl-3,4′-bipyridin-6-yl)carbonyl]amino}phenyl)methyl]- 1-piperazinecarboxylate Similar toD103 although 2 eq. boronic acid used and reaction time was 20 minutes.516.2 D131 D72

1,1-dimethylethyl (2S)-4-({4- [{[5-(4-fluorophenyl)-2-pyridinyl]carbonyl}(methyl) amino]phenyl} methyl)-2-methyl-1-piperazinecarboxylate Similar to D103 although 1 eq. boronic acid usedand reaction temperature/time was 150° C./ 5 minutes. 519.2 D132 D72

1,1-dimethylethyl (2S)-4-({4-[{[5-(3- cyanophenyl)-2-pyridinyl]carbonyl}(methyl) amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate Similar to D103 although 1 eq. boronicacid used and reaction temperature/time was 150° C./ 5 minutes. 526.2D133 D72

1,1-dimethylethyl (2S)-2-methyl-4- ({4-[methyl({5-[3-(methyloxy)phenyl]-2-pyridinyl}carbonyl)amino] phenyl}methyl)-1-piperazinecarboxylate Similar to D103 although 1 eq. boronic acid usedand reaction temperature/ time was 150° C./ 5 minutes. 531.4 D134 D72

1,1-dimethylethyl (2S)-2-methyl-4- ({4-[methyl({5-[4-(methyloxy)phenyl]-2-pyridinyl} carbonyl)amino]phenyl}methyl)-1-piperazinecarboxylate Similar to D103 although 1 eq. boronic acid usedand reaction temperature/ time was 150° C./ 5 minutes. 531.4 D135 D72

1,1-dimethylethyl (2S)-4-({4- [{[5-(3-fluorophenyl)-2-pyridinyl]carbonyl}(methyl) amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate Similar to D103 although 1 eq. boronicacid used and reaction temperature/ time was 150° C./ 5 minutes. 519.3D136 D108

1,1-dimethylethyl (2S)-2-methyl-4- [(4-{methyl[2′-methyl-2,4′-bipyridin-5-yl)carbonyl]amino}phenyl) methyl]-1- piperazinecarboxylate Similar toD103 although 2 eq. boronic acid used and reaction time was 20 minutes.516.4

Description 137 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methyl{[4-(2-pyridinyl)phenyl]carbonyl}amino)phenyl]methyl}-1-piperazinecarboxylate(D137)

To 4-(2-pyridinyl)benzoic acid (0.0624 g, 0.313 mmol) in DMF (3 mL) wasadded N-benzyl-N′-cyclohexylcarbodiimide resin (0.294 g, 1.6 mmol/g,0.47 mmol), 1-hydroxybenzotriazole (0.064 g, 0.47 mmol) and DCM (1 mL)and the mixture was shaken for 30 minutes. 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazine-carboxylate(D3) (100 mg, 0.313 mmol), DMF (3 mL) and DCM (1 mL) were then added andthe mixture was shaken for ˜2 days at room temperature The reactionmixture was filtered to remove the resin which was then washed withfurther DMF/DCM (3:1). The filtrate was concentrated to give the crudeproduct which was purified by column chromatography. Elution with anether/pentane gradient yielded the title compound (0.055 g). MS (ES):MH⁺ 501.2.

Tabulated compounds D138-D140 were prepared from dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) and the appropriate carboxylic acid using methods similar to thatdescribed in for D137 in Description 137.

Description Structure Name MH⁺ D138

1,1-dimethylethyl (2S)-2-methyl- 4-{[4-(methyl{[4-(2-pyrimidinyl)phenyl]carbonyl}amino) phenyl]methyl}-1-piperazinecarboxylate 502.2 D139

1,1-dimethylethyl (2S)-2-methyl- 4-{[4-(methyl{[4-(1H-pyrazol-1-yl)phenyl]carbonyl}amino)phenyl] methyl}-1-piperazinecarboxylate 490.4D140

1,1-dimethylethyl (2S)-2-methyl- 4-{[4-(methyl{[6-(1H-pyrrol-1-yl)-3-pyridinyl]carbonyl}amino)phenyl] methyl}-1-piperazinecarboxylate 490.4

Description 141 1,1-Dimethylethyl(2S)-2-methyl-4-{[4-(methyl{[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}amino)phenyl]methyl}-1-piperazinecarboxylate(D141)

To 1,1-dimethylethyl(2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate(D3) (100 mg, 0.313 mmol) in DMF (3 mL) wasN-benzyl-N′-cyclohexylcarbodiimide resin (0.294 g, 1.6 mmol/g, 0.47mmol), 1-hydroxybenzotriazole (0.064 g, 0.47 mmol) and DCM (1 mL). Themixture was stirred for 30 minutes and4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (0.064 g, 0.313 mmol), DCM(2 mL) and DMF (6 mL) were added. The reaction mixture was stirred for22 h at room temperature. PS-trisamine resin (0.179 g, 0.626 mmol),PS-isocyanate resin (0.298 g, 0.626 mmol) and MP-carbonate resin (0.788g, 2.35 mmol) were added and the mixture stirred for 2 h at roomtemperature. The mixture was filtered to remove the resins and thefiltrate was concentrated to give the crude product which was purifiedby column chromatography. Elution with 10-60% EtOAc/pentane gave thetitle compound. MS (ES): MH⁺ 506.2.

Example 16-(3-Fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E1)

1,1-Dimethylethyl(2S)-4-({4-[{[6-(3-fluorophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D60) (0.127 g, 0.245 mmol) was stirred in DCM (10 mL) and TFA (2.5 mL)was added drop-wise. The reaction mixture was stirred for ˜1 h, thenconcentrated in vacuo and re-diluted with DCM and water. The separatedaqueous layer was basified to pH14 with concentrated NaOH solution, thenextracted with DCM which was dried (Na₂SO₄) and concentrated to yieldthe title compound as a yellow oil (0.091 g). δ_(H) (CDCl₃, 400 MHz)8.52 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.54 (1H, d), 7.40 (1H, m),7.25 (2H, d), 7.09 (1H, m), 7.03 (2H, d), 3.53 (3H, s), 3.41 (2H, s),2.83 (3H, m), 2.66 (2H, d), 1.96 (1H, td), 1.62 (1H, m), 1.55 (br.s),0.97 (3H, d), NH not observed. MS (ES): MH⁺ 419.2.

This whole was dissolved in MeOH and treated with 1 M HCl in Et₂O (0.218mL) to give the hydrochloride salt of the title compound as an off-whitesolid (0.092 g). MS (ES): MH⁺ 419.2.

Example 26-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E2)

1,1-Dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D16) (0.518 g, 0.97 mmol) was dissolved in DCM (19.2 mL) and TFA (4.8mL) added. The solution was stirred for 1.5 h then the solvent wasremoved in vacuo. The product was taken up in methanol and elutedthrough an SCX (10 g) column with 2M NH₃ in methanol solution. Thesolvent was removed to give a colourless oil which was purified bycolumn chromatography. Elution with a 0-5% (2M NH₃ in methanol)/DCMgradient yielded the title compound as a colourless oil (0.379 g). δ_(H)(CDCl₃, 400 MHz) 8.07 (1H, dd), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H,m), 6.70 (1H, d), 3.48 (3H, s), 3.43 (2H, s), 3.13 (br.s), 2.95 (3H, m),2.70 (2H, d), 2.04 (1H, m), 1.74 (1H, m), 1.05 (3H, d). MS (ES): MH⁺435.3.

This whole was dissolved in DCM and treated with 1 M HCl in Et₂O (0.873mL) to give the hydrochloride salt of the title compound as a pale creamsolid (0.345 g). MS (ES): MH⁺ 435.2.

Example 2 Alternative Method (A)6-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E2)

A solution of 1,1-dimethylethyl(2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D16) (32.39 g, 0.0606 mol) in DCM (150 mL) was cooled in an ice/waterbath and TFA (80 mL) was added drop-wise over 10 minutes. The reactionmixture was stirred at room temperature overnight then concentrated to ayellow gum. The gum was dissolved in MeOH (100 mL) and loaded onto SCXresin (150 g, pre-washed with MeOH). Elution with MeOH (750 mL) gaveunchanged TFA salt of the title compound, and elution with 2M NH₃ inMeOH (750 mL) gave title compound free base. The recovered TFA salt wastreated in a similar manner to that described above using further SCXresin (100 g) to give a further batch of title compound free base. Thetwo batches of the free base were combined in DCM and concentrated togive the title compound as a pale yellow gum (26.78 g). δ_(H) (CDCl₃,400 MHz) 8.07(1H, d), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H, m), 6.70(1H, d), 3.48 (3H, s), 3.42 (2H, s), 2.89 (3H, m), 2.68 (2H, d), 1.97(1H, m), 1.64 (1H, t), 1.49 (1H bs), 1.00 (3H, d). MS (ES): MH⁺ 435.1.

A solution of E2 free base (25.74 g, 0.0592 mol) was dissolved in MeOH(250 mL) at room temperature, flushed with argon wastreated with 1 M HClin Et₂O (59.2 mL). The solution was concentrated in vacuo to give a palebrown foam which was dried overnight at 60° C. in vacuo. 26.4 g of thismaterial was dissolved in DCM (175 mL) and added dropwise over 30minutes to vigorously stirred hexane (2.65 L) under an argon atmosphere.Stirring was discontinued and the precipitate was isolated by filtrationunder argon, washed with hexane (2×2 L), filtered under a gentle vacuumwith an argon blanket and then dried in vacuo at 80° C. overnight. Theresulting solid was dissolved in water (220 mL), freeze-driedover-weekend, ground to a powder and dried in vacuo at 80-82° C.overnight. The powder was re-dissolved in water (150 mL), freeze-driedovernight and then ground to a powder yielding the hydrochloride salt ofthe title compound as a cream solid (24.13 g)

Example 2B Method 16-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamidefumarate (E2B)

A solution of E2 free base (57.5 mg) in methyl iso-butylketone (0.5 mL)was added to fumaric acid (13.4 mg). Further methyl iso-butylketone (0.5mL) was added and the mixture was heated with a hot air gun. Theresulting yellow gum was scratched with a spatula and a small amount ofwhite solid appeared throughout the gum. The sample was placed on ashaker block and temperature cycled (0-40° C. in 1 h blocks) over theweekend. To the resulting yellow gum in a colourless solution was added1,4-dioxane (0.5 mL) and the mixture was heated to dissolve the gum. Oncooling a gum formed and the sample was temperature cycled as before.After a period of ˜6 weeks a white solid slurry had formed. The mixturewas placed back in the shaker block and temperature cycled as before,overnight. The mixture was then left to equilibrate to room temperatureand the white solid was collected by filtration. After drying at 40° C.under vacuum overnight the title compound was obtained as a white,mainly crystalline powder (38.7 mg). M.pt. onset ˜150° C.

Example 2B Method 26-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamidefumarate (E2B)

A mixture of E2 free base (413.7 mg) and fumaric acid (107.4 mg) inmethyl iso-butylketone (8 mL) and 1,4-dioxane (4 mL) was heated with ahot air gun giving a yellow solution. On cooling, a white gummyprecipitate formed so the mixture was re-heated to dissolve the gum andthen seeded with the previously obtained fumarate salt from Method 1. Oncooling, a gum formed so further 1,4-dioxane (2 mL) was added and themixture heated to dissolve the gum. Further seeds were added at ˜60° C.and the mixture was temperature cycled (0-40° C. in 1 h blocks butstarting at 40° C.) over the weekend. To the resulting ‘milk-like’slurry was added further 1,4-dioxane (1.5 mL), the sides of the vesselwere scratched and the mixture was then temperature cycled as before.After 9 days, the slurry was filtered and the filter cake wasde-liquored over ˜90 minutes to give a white solid which was dried at40° C. under vacuum. After 20 h the title compound was obtained aswhite, mainly crystalline, powder (377.2 mg). M.pt. 141° C., XPRD seeFIG. 1

Example 2B Method 36-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamidefumarate (E2B)

A mixture of E2 free base (201.9 mg) and fumaric acid (53.9 mg) in EtOAc(2 mL) was stirred at room temperature. After 5 minutes, a milkygelatinous precipitate started to form so further EtOAc (2 mL) was addedtogether with seed crystals of the previously obtained fumarate saltfrom Method 2. After 1 h, the precipitate became very thick andgelatinous so further EtOAc (2 ml) and seed crystals were added. Themixture was stirred at room temperature for 0.5 h, then warmed to 40° C.for 0.5 h. Further EtOAc (5 mL) was added and stirring was continued at40° C. for 10 minutes then at 60° C. for 2 h. The mixture was cooled to50° C. for ˜1 h then to 40° C. for ˜1 h then to room temperatureovernight. The solid was filtered off under argon, washed with EtOAc,semi-dried under argon and then dried at 60° C. under vacuum to give thetitle compound (164 mg).

Example 2B Method 46-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamidefumarate (E2B)

A partial suspension/solution of finely ground fumaric acid (267 mg) inEtOAc (10 mL) was stirred and heated at 60° C. This was addedportionwise to a solution of E2 free base (0.9997 g) in EtOAc (20 ml)heated at 70° C. Any initial turbidity/gum rapidly disappeared but asaddition continued the solution stayed slightly turbid. At this pointthe solution was seeded with the previously obtained fumarate salt fromMethod 3 and within a few minutes a heavy crystalline precipitatestarted to form. Addition of the fumaric acid suspension/solutioncontinued over ˜3 h. The reaction mixture was stirred at 70° C. for afurther one hour then slowly allowed to cool to room temperatureovernight with stirring. The solid was collected by filtration, washedwith EtOAc, dried under argon then further dried at 60° C., undervacuum, overnight to give the title compound (1.077 g). δ_(H) (CD₃OD,400 MHz) 7.95 (1H, d), 7.74 (1H, dd), 7.31 (2H, d), 7.17 (2H, d), 7.14(2H, t), 7.05 (2H, dd), 6.78 (1H, d), 6.68 (2H, s), 3.56 (2H, s), 3.46(3H, s), 3.30 (2H+ MeOH, m), 3.11 (1H, m), 2.89 (2H, m), 2.32 (1H, m),2.10 (1H, dd), 1.25 (3H, d) (NH not observed). M.pt. ??° C., XPRD seeFIG. 2.

Example 31-(4-Fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide(E3)

To 1,1-dimethylethyl(2S)-4-({4-[{[1-(4-fluorophenyl)-4-piperidinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D59) (0.19 g, 0.36 mmol) in DCM (5 mL), cooled in an ice bath, wasadded TFA (1.5 mL) and the reaction mixture was then stirred for 3 h atroom temperature. The solvent was removed and the crude product waseluted through an SCX cartridge with methanol then 2M NH₃ in methanol togive a yellow oil which was further purified by column chromatography.Elution with 0-5% (2M NH₃ in methanol)/DCM yielded the title compound asa yellow oil (0.13 g). δ_(H) (MeOD, 250 MHz) 7.48 (2H, d), 7.30 (2H, d),7.13 (2H, d), 6.84 (2H, d), 3.59 (4H, m), 3.23 (3H, s), 3.18 (2H, d),3.01 (1H, m), 2.90 (2H, t), 2.31 (4H, m), 2.02 (1H, m), 1.85 (2H, m),1.70 (2H, d), 1.17 (3H, d) [NH not observed]. MS (ES): MH⁺ 425.2.

This whole was dissolved in DCM and treated with 1 M HCl in Et₂O (0.337mL) to give the hydrochloride salt of the title compound as a whitesolid (0.1 g). MS (ES): MH⁺ 425.1

The following tabulated examples E4-E37 were prepared from theappropriate Boc-protected intermediate as indicated in the table, usingmethods similar to those described for Example 1, 2 or 3.

Prepared Example from Boc No. intermediate: Structure E4 D61

E5 D17

E6 D18

E7 D19

E8 D20

E9 D21

E10 D22

E11 D23

E12 D24

E13 D25

E14 D26

E15 D27

E16 D28

E17 D29

E18 D30

E19 D31

E20 D32

E21 D15

E22 D33

E23 D34

E24 D35

E25 D36

E26 D37

E27 D58

E28 D38

E29 D39

E30 D40

E31 D41

E32 D42

E33 D43

E34 D45

E35 D56

E36 D55

E37 D46

Example No. Name Method Comment MH+ E46-(4-fluorophenyl)-N,2-dimethyl-N-(4- Similar method to E1 433.2{[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-3- pyridinecarboxamide E56-(4-fluorophenyl)-N-methyl-N-(4- Similar method to E1 with 419.1{[(3S)-3-methyl-1- column chromatography piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E6 N-methyl-N-(4-{[(3S)-3-methyl-1- Similar methodto E1 410.3 piperazinyl]methyl}phenyl)-6-(4-morpholinyl)-3-pyridinecarboxamide E7 4′-fluoro-N-methyl-N-(4-{[(3S)-3-Similar method to E1 418.3 methyl-1-piperazinyl]methyl}phenyl)-4-biphenylcarboxamide E8 6-(4-fluorophenyl)-2-methyl-N-(4- Similarmethod to E1 with 419.3 {[(3S)-3-methyl-1- reaction time of ~2.3 hpiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E91-[(3-fluorophenyl)carbonyl]-N- Similar method to E1 453.2methyl-N-(4-{[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-4-piperidinecarboxamide E10 1-[(3-fluorophenyl)methyl]-N-methyl- Similarmethod to E1 with 439.3 N-(4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-4- piperidinecarboxamide E111-(4-chlorophenyl)-N-methyl-N-(4- Similar method to E3 but no 441.1{[(3S)-3-methyl-1- column chromatography piperazinyl]methyl}phenyl)-4-piperidinecarboxamide E12 N-methyl-N-(4-{[(3S)-3-methyl-1- Similarmethod to E1 with 408.3 piperazinyl]methyl}phenyl)-6-(1- reaction timeof 3.5 h and piperidinyl)-3-pyridinecarboxamide column chromatographyE13 6-(2-fluorophenyl)-N-methyl-N-(4- Similar method to E1 419.2{[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-3- pyridinecarboxamide E146-(2,4-difluorophenyl)-N,2-dimethyl- Similar method to E1 with 451.2N-(4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E156-(3,4-difluorophenyl)-N,2-dimethyl- Similar method to E1 with 451.2N-(4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E166-(3-fluorophenyl)-N,2-dimethyl-N-(4- Similar method to E1 with 433.2{[(3S)-3-methyl-1- column chromatography piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E17 4-[(3-fluorophenyl)oxy]-N-methyl-N- Similarmethod to E3 with 434.1 (4-{[(3S)-3-methyl-1- reaction time of 2 h andno piperazinyl]methyl}phenyl)benzamide column chromatography E186-(3-cyanophenyl)-N,2-dimethyl-N-(4- Similar method to E1 with 440.3{[(3S)-3-methyl-1- column chromatography piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E19 6-(4-cyanophenyl)-N,2-dimethyl-N-(4- Similarmethod to E1 with 440.3 {[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E204-[(4-fluorophenyl)oxy]-N-methyl-N- Similar method to E3 with 434.1(4-{[(3S)-3-methyl-1- reaction time of 3.5 h and nopiperazinyl]methyl}phenyl)benzamide column chromatography E21N-(4-{[(3R,5S)-3,5-dimethyl-1- Similar method to E2 447.3piperazinyl]methyl}phenyl)-6-(4- fluorophenyl)-N,2-dimethyl-3-pyridinecarboxamide E22 2-[(4-fluorophenyl)oxy]-N-methyl-N- Similarmethod to E3 with 434.1 (4-{[(3S)-3-methyl-1- reaction time of 3.5 hpiperazinyl]methyl}phenyl)benzamide E23 N-(4-{[(3R,5S)-3,5-dimethyl-1-Similar method to E2 with 433.2 piperazinyl]methyl}phenyl)-6-(4-reaction time of 2 h fluorophenyl)-N-methyl-3- pyridinecarboxamide E244-[(2-fluorophenyl)oxy]-N-methyl-N- Similar method to E3 with 434.2(4-{[(3S)-3-methyl-1- reaction time of 5 h and nopiperazinyl]methyl}phenyl)benzamide column chromatography E253-[(4-fluorophenyl)oxy]-N-methyl-N- Similar method to E3 with 434.2(4-{[(3S)-3-methyl-1- reaction time of 5 h and nopiperazinyl]methyl}phenyl)benzamide column chromatography E263-[(3-fluorophenyl)oxy]-N-methyl-N- Similar method to E3 with 434.2(4-{[(3S)-3-methyl-1- reaction time of 1.5 h and nopiperazinyl]methyl}phenyl)benzamide column chromatography E276-[(4-fluorophenyl)amino]-N-methyl- Similar method to E2 but no 434.2N-(4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E282-(4-fluorophenyl)-N,4-dimethyl-N-(4- Similar method to E1 with 434.3{[(3S)-3-methyl-1- reaction time of 1.5 h andpiperazinyl]methyl}phenyl)-5- column chromatographypyrimidinecarboxamide E29 2-(4-fluorophenyl)-N-methyl-N-(4- Similarmethod to E1 with 420.3 {[(3S)-3-methyl-1- reaction time of 1.5 hpiperazinyl]methyl}phenyl)-5- pyrimidinecarboxamide E306-(4-fluorophenyl)-N,2-dimethyl-N-(4- Similar method to E2 433.2{[(3R)-3-methyl-1- piperazinyl]methyl}phenyl)-3- pyridinecarboxamide E316-(4-fluorophenyl)-N-methyl-N-(4- Similar method to E2 with 419.2{[(3R)-3-methyl-1- purification by MDAP piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E32 4′-fluoro-N-methyl-N-(4-{[(3S)-3- Similar methodto E1 with 418.2 methyl-1-piperazinyl]methyl}phenyl)- columnchromatography 3-biphenylcarboxamide E334′-fluoro-N-methyl-N-(4-{[(3S)-3- Similar method to E1 with 418methyl-1-piperazinyl]methyl}phenyl)- column chromatography2-biphenylcarboxamide E34 6-(3-fluorophenyl)-N-methyl-N-[4-(1- Similarmethod to E2 but no 405.2 piperazinylmethyl)phenyl]-3- columnchromatography pyridinecarboxamide E356-[(3-fluorophenyl)oxy]-N-methyl-N- Similar method to E2 with 435.2(4-{[(3S)-3-methyl-1- reaction time of 1 h and nopiperazinyl]methyl}phenyl)-3- column chromatography pyridinecarboxamideE36 6-[(2-fluorophenyl)oxy]-N-methyl-N- Similar method to E2 but no435.2 (4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E376-(3-fluorophenyl)-N,2-dimethyl-N-[4- Similar method to E2 but no 419.2(1-piperazinylmethyl)phenyl]-3- column chromatographypyridinecarboxamide

Example 38 and Example 396-(2-Cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E38)

and

6-[2-(Aminocarbonyl)phenyl]-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E39)

1,1-Dimethylethyl(2S)-4-({4-[{[6-(2-cyanophenyl)-2-methyl-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D44) (0.309 g, 0.573 mmol) was stirred in DCM (20 mL) and TFA (5 mL)was added drop-wise. The reaction mixture was stirred for ˜1 h, thenconcentrated in vacuo and re-diluted with DCM and water. The separatedaqueous layer was basified to pH14 with concentrated NaOH solution, thenextracted with DCM which was dried (Na₂SO₄) and concentrated to give thecrude product which was purified by column chromatography. Elution with0-10% MeOH/DCM yielded E38 as a pink oil (0.219 g). MS (ES): MH⁺ 440.3.

This whole was taken up in MeOH and 1 M HCl in Et₂O (0.598 mL) added.The solvent was removed to give a crude product mixture which waspurified by MDAP to yield the crude formate salts of the title compoundsE38 and E39. E38 formate salt was passed through an SCX cartridgeeluting with methanol then 2M NH₃ in methanol yielding E38 free base(0.051 g) as a white solid. δ_(H) (CDCl₃, 400 MHz) 7.75 (2H, m), 7.64(1H, m), 7.43 (3H, m), 7.16 (2H, d), 6.98 (2H, d), 3.65 (3H, s), 3.36(2H, s), 2.83 (3H, m), 2.63 (5H, m), 1.91 (1H, m), 1.59 (1H, m), 1.35(br.s) 0.95 (3H, d). MS (ES): MH⁺ 440.3.

E39 formate salt was passed through an SCX cartridge eluting withmethanol then 2M NH₃ in methanol yielding crude E39 free base (0.026 g)as a colourless oil which was further purified by column chromatography.Elution with 0-10% (2M NH₃ in methanol)/DCM yielded E39 free base as acolourless oil (0.024 g). δ_(H) (MeOH, 400 MHz) 7.50 (5H, br.d), 7.23(3H, m), 7.16 (2H, m), 3.51 (3H, s), 3.14 (2H, s), 3.35 (3H, s), 2.82(3H, m), 2.64 (2H, m), 2.51 (3H, s), 1.96 (1H, m), 1.56 (1H, m), 0.95(3H, d). MS (ES): MH⁺ 458.1. E39 free base was dissolved in MeOH andtreated with 1 M HCl in Et₂O (0.058 mL) to give the hydrochloride saltof E39 as a light yellow solid (0.011 g). MS (ES): MH⁺ 458.1.

Example 406-(2-Cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E40)

1,1-Dimethylethyl(2S)-4-({4-[{[6-(2-cyanophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate(D49) (0.091 g, 0.173 mmol) was stirred in DCM (10 mL) and TFA (2.5 mL)was added drop-wise. The reaction mixture was stirred for ˜1 h, thenconcentrated in vacuo and re-diluted with DCM and water. The separatedaqueous layer was basified to pH14 with concentrated NaOH solution, thenextracted with DCM which was dried (Na₂SO₄) and concentrated to give thecrude product which was purified by column chromatography. Elution with0-10% MeOH/DCM yielded the title compound as a colourless oil (0.054 g).δ_(H) (CDCl₃, 400 MHz) 8.59 (1H, s), 7.83 (1H, dd), 7.78 (2H, m), 7.67(1H, m), 7.50 (1H, m), 7.23 (2H, d), 7.05 (2H, d), 3.54 (3H, s), 3.45(2H, s), 2.89-3.02 (3H, m), 2.71 (2H, m), 2.09 (1H, t), 1.79 (1H, t),1.75 (br.s) 1.07 (3H, d).MS (ES): MH⁺ 426.2.

The title compound (0.054 g) was dissolved in MeOH (0.54 mL). A portionof this solution (0.20 mL) was treated with 1 M HCl in Et₂O but thisresulted in partial decomposition to the corresponding 2-primary amidecompound. The remaining MeOH solution (0.34 mL) was re-concentrated anddried in vacuo to give the title compound as an off-white solid.

The following tabulated examples E41-E53 were prepared from theappropriate Boc-protected intermediate as indicated in the table, usingmethods similar to those described for Example 1, 2 or 3.

Prepared Example from Boc No. intermediate: Structure E41 D47

E42 D48

E43 D57

E44 D50

E45 D73

E46 D74

E47 D69

E48 D75

E49 D76

E50 D51

E51 D52

E52 D53

E53 D71

E54 D111

E55 D112

E56 D113

E57 D114

E58 D115

E59 D116

E60 D117

E61 D124

E62 D125

E63 D127

E64 D129

E65 D141

E66 D121

E67 D122

E68 D126

E69 D128

E70 D109

E71 D131

E72 D132

E73 D133

E74 D134

E75 D135

E76 D110

Example No. Name Method Comment MH+ E416-(3-fluorophenyl)-N-methyl-N-(3- Similar method to E1 with 433.2methyl-4-{[(3S)-3-methyl-1- reaction time of 1.5 hpiperazinyl]methyl}phenyl)-3- pyridinecarboxamide E426-(3-cyanophenyl)-N-methyl-N-(4- Similar method to E1 with 426.3{[(3S)-3-methyl-1- column chromatography piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E43 6-[(3-cyanophenyl)oxy]-N-methyl-N-(4- Similarmethod to E2 with 442.2 {[(3S)-3-methyl-1- reaction time of 2 h and aq.piperazinyl]methyl}phenyl)-3- work-up using DCM/sat. aq.pyridinecarboxamide NaHCO₃ solution followed by column chromatographyand MDAP purification. E44 N-(2-fluoro-4-{[(3S)-3-methyl-1- Similarmethod to E1 with 437.1 piperazinyl]methyl}phenyl)-6-(3- reaction timeof 2-3 h and aq. fluorophenyl)-N-methyl-3- work-up using DCM/2M NaOH.pyridinecarboxamide Salt formation in EtOAc. E455-[(4-fluorophenyl)oxy]-N-methyl-N-(4- Similar method to E2 with 435.2{[(3S)-3-methyl-1- reaction time of 2 h and aq.piperazinyl]methyl}phenyl)-2- work-up using DCM/sat. aq.pyridinecarboxamide NaHCO₃ solution followed by MDAP purification. E465-[(3-fluorophenyl)oxy]-N-methyl-N-(4- Similar method to E2 with 435.2{[(3S)-3-methyl-1- reaction time of 2 h and aq.piperazinyl]methyl}phenyl)-2- work-up using DCM/sat. aq.pyridinecarboxamide NaHCO₃ solution followed by MDAP purification. E47N-(2-fluoro-4-{[(3S)-3-methyl-1- Similar method to E1 with aq. 453.2piperazinyl]methyl}phenyl)-6-[(4- work-up using DCM and 2Mfluorophenyl)oxy]-N-methyl-3- NaOH. Salt formation inpyridinecarboxamide EtOAc. E48 5-[(3-cyanophenyl)oxy]-N-methyl-N-(4-Similar method to E2 with 442.2 {[(3S)-3-methyl-1- reaction time of 2 hand aq. piperazinyl]methyl}phenyl)-2- work-up using DCM/sat. aq.pyridinecarboxamide NaHCO₃ solution followed by column chromatography.E49 5-[(4-fluorophenyl)amino]-N-methyl-N- Similar method to E2 with aq.434.2 (4-{[(3S)-3-methyl-1- work-up using DCM and sat.piperazinyl]methyl}phenyl)-2- aq. NaHCO₃ solution followedpyridinecarboxamide by column chromatography. E501-[(3,4-difluorophenyl)methyl]-N- Similar method to E1 with 457.2methyl-N-(4-{[(3S)-3-methyl-1- column chromatographypiperazinyl]methyl}phenyl)-4- followed by chromatographypiperidinecarboxamide using Biotage KP-NH ™ column* E511-[(4-fluorophenyl)methyl]-N-methyl-N- Similar method to E1 with 439.2(4-{[(3S)-3-methyl-1- chromatography using Biotagepiperazinyl]methyl}phenyl)-4- KP-NH ™ column piperidinecarboxamide E52N-(3-fluoro-4-{[(3S)-3-methyl-1- Similar method to E1 with 437.1piperazinyl]methyl}phenyl)-6-(3- reaction time of 4 h and aq.fluorophenyl)-N-methyl-3- work-up using DCM/2M NaOH. pyridinecarboxamideSalt formation in DCM. E53 N-(3-fluoro-4-{[(3S)-3-methyl-1- Similarmethod to E1 with 453.1 piperazinyl]methyl}phenyl)-6-[(4- reaction timeof 4 h and aq. fluorophenyl)oxy]-N-methyl-3- work-up using DCM/2M NaOH.pyridinecarboxamide Salt formation in DCM. E541-[(3-cyanophenyl)methyl]-N-methyl-N- Similar method to E1 with 446.4(4-{[(3S)-3-methyl-1- reaction time of 0.5 hpiperazinyl]methyl}phenyl)-4- piperidinecarboxamide E551-[(4-cyanophenyl)methyl]-N-methyl-N- Similar method to E1 with 446.4(4-{[(3S)-3-methyl-1- reaction time of 0.5 hpiperazinyl]methyl}phenyl)-4- piperidinecarboxamide E566-(3-fluorophenyl)-N-(1-methylethyl)-N- Similar method to E1 with 447.3(4-{[(3S)-3-methyl-1- reaction time of 2 h piperazinyl]methyl}phenyl)-3-pyridinecarboxamide E57 N-ethyl-6-(3-fluorophenyl)-N-(4-{[(3S)- Similarmethod to E1 with 433.2 3-methyl-1-piperazinyl]methyl}phenyl)- reactiontime of 3 h 3-pyridinecarboxamide E58 6-(3-fluorophenyl)-N-[2- Similarmethod to E1 with 463.3 (methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-chromatography using Biotage 1-piperazinyl]methyl}phenyl)-3- KP-NH ™column pyridinecarboxamide E59 6-[(4-fluorophenyl)oxy]-N-methyl-N-(3-Similar method to E1 with 449.3 methyl-4-{[(3S)-3-methyl-1- reactiontime of 0.5 h and piperazinyl]methyl}phenyl)-3- column chromatographypyridinecarboxamide E60 6-(3-fluorophenyl)-N-methyl-N-(5- Similar methodto E1 with 420.2 {[(3S)-3-methyl-1-piperazinyl]methyl}- columnchromatography 2-pyridinyl)-3-pyridinecarboxamide E616-[(4-fluorophenyl)oxy]-N-methyl-N-(5- Similar method to E1 with 436.2{[(3S)-3-methyl-1-piperazinyl]methyl}- reaction time of 0.5 h and2-pyridinyl)-3-pyridinecarboxamide column chromatography E626-[(4-fluorophenyl)oxy]-N-methyl-N-(4- Similar method to E1 with 435.2{[(3S)-3-methyl-1- reaction time of 2 h and columnpiperazinyl]methyl}phenyl)-2- chromatography. Salt formationpyridinecarboxamide in DCM/MeOH E636-(4-fluoro-1-piperidinyl)-N-methyl-N- Similar method to E1 with 426.2(4-{[(3S)-3-methyl-1- reaction time of 2 h and columnpiperazinyl]methyl}phenyl)-3- chromatography. Salt formationpyridinecarboxamide in DCM/MeOH E64 6-(3-fluorophenyl)-N-methyl-N-(4-Similar method to E1 with 419.2 {[(3S)-3-methyl-1- reaction time of 2 h.Salt piperazinyl]methyl}phenyl)-2- formation in DCM/MeOHpyridinecarboxamide E65 N-methyl-4-(3-methyl-1,2,4-oxadiazol- Similarmethod to E1 with 406.3 5-yl)-N-(4-{[(3S)-3-methyl-1- reaction time of 3h. Salt piperazinyl]methyl}phenyl)benzamide formation in DCM/MeOH E66N-ethyl-6-[(4-fluorophenyl)oxy]-N-(4- Similar method to E1 with 449.4{[(3S)-3-methyl-1- reaction time of 1.5 h. Saltpiperazinyl]methyl}phenyl)-3- formation in DCM. pyridinecarboxamide E67N-methyl-N-(4-{[(3S)-3-methyl-1- Similar method to E1 with SCX 418.1piperazinyl]methyl}phenyl)-6-(3- purification. Salt formation inpyridinyloxy)-3-pyridinecarboxamide DCM/MeOH E686-[(3-fluorophenyl)oxy]-N-methyl-N-(4- Similar method to E1 with 435.2{[(3S)-3-methyl-1- reaction time of 2 h, SCX andpiperazinyl]methyl}phenyl)-2- column chromatography. Saltpyridinecarboxamide formation in DCM/MeOH E696-(4,4-difluoro-1-piperidinyl)-N-methyl- Similar method to E1 with 444.1N-(4-{[(3S)-3-methyl-1- reaction time of 2 h and MDAPpiperazinyl]methyl}phenyl)-3- purification. Salt formation inpyridinecarboxamide DCM/MeOH E70 6-[(4-fluorophenyl)oxy]-N-methyl-N-(6-Similar method to E2 with 436.3 {[(3S)-3-methyl-1-piperazinyl]methyl}-reaction time of 2 h. 3-pyridinyl)-3-pyridinecarboxamide E715-(4-fluorophenyl)-N-methyl-N-(4- Similar method to E2 with 419.3{[(3S)-3-methyl-1- reaction time of 2 h. piperazinyl]methyl}phenyl)-2-pyridinecarboxamide E72 5-(3-cyanophenyl)-N-methyl-N-(4- Similar methodto E2. 426.2 {[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-2-pyridinecarboxamide E73 N-methyl-5-[3-(methyloxy)phenyl]-N-(4- Similarmethod to E2 with 431.2 {[(3S)-3-methyl-1- reaction time of 2 h.piperazinyl]methyl}phenyl)-2- pyridinecarboxamide E74N-methyl-5-[4-(methyloxy)phenyl]-N-(4- Similar method to E2 with 431.2{[(3S)-3-methyl-1- reaction time of 2 h. piperazinyl]methyl}phenyl)-2-pyridinecarboxamide E75 5-(3-fluorophenyl)-N-methyl-N-(4- Similar methodto E2 with 419.2 {[(3S)-3-methyl-1- reaction time of 2 h and nopiperazinyl]methyl}phenyl)-2- column chromatography. pyridinecarboxamideE76 6-(4-fluorophenyl)-N-methyl-N-(6- Similar method to E2 with 420.3{[(3S)-3-methyl-1-piperazinyl]methyl}- reaction time of 3 h and MDAP3-pyridinyl)-3-pyridinecarboxamide purification instead of columnchromatography

Example 776-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-methyl-5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide(E77)

1,1-Dimethylethyl(2S)-4-({6-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]-4-methyl-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate(D118) (26 mg, 0.047 mmol) was dissolved in dry DCM (4 mL). TFA (1 mL)was added and the reaction mixture was stirred at room temperature,under argon. The reaction mixture was concentrated, re-dissolved inmethanol (2 mL) and loaded on to a 1 g SCX cartridge. Elution withmethanol (20 mL) followed by 2M NH₃ in methanol (20 mL) gave acolourless oil. The product was further purified by MDAP. The resultingoil was dissolved in methanol (1 mL) and loaded on to a 1 g SCXcartridge and eluted with methanol (20 mL), followed by 2M NH₃ inmethanol (20 mL) to give the title compound as a colourless oil (15 mg).MS (ES): MH⁺ 450.1.

This whole was dissolved in MeOH (1 mL) and treated with 1 M HCl in Et₂O(0.037 mL) to give the hydrochloride salt of the title compound as awhite solid (13.6 mg). MS (ES): MH⁺ 450.3.

Example 78N,2′-Dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3,4′-bipyridine-6-carboxamide(E78)

The title compound was prepared from 1,1-dimethylethyl(2S)-2-methyl-4-[(4-{methyl[(2′-methyl-3,4′-bipyridin-6-yl)carbonyl]amino}phenyl)methyl]-1-piperazinecarboxylate(D130) using a procedure similar to that described for E1 in Example 1although hydrochloride salt preparation was carried out in DCM/MeOH(1:1). δ_(H) (MeOD, 400 MHz) 8.96 (1H, br.m), 8.76 (1H, d), 8.39 (1H,br.m), 8.33 (1H, s), 8.23 (1H, d), 7.81 (1H, br.d), 7.58 (2H, br.s),7.36 (2H, br.s), 3.86 (1H, br.s), 3.58-3.71 (4H, m), 3.54 (3H, s), 3.44(1H, m), 3.34 (2H, s), 3.30 (1H, m), 2.85 (3H, s), 1.40 (3H, d), NH notobserved. MS (ES⁺): 316.1, no molecular ion (MH⁺) observed.

Example 796-[(4-Fluorophenyl)oxy]-N-[2-(methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide(E79)

1,1-Dimethylethyl(2S)-4-[(4-{({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)[2-(methyloxy)ethyl]amino}phenyl)methyl]-2-methyl-1-piperazinecarboxylate (D119) (0.077 g, 0.13 mmol) was dissolved in 4M HCl indioxane (5 mL). A few drops of water were added and the reaction wasstirred for 2 h. The solvent was removed in vacuo and the resultingyellow oil was dissolved in MeOH and loaded onto an SCX cartridge whichwas eluted with DCM, MeOH and 2M NH₃ in MeOH. The ammoniacal fractionswere combined and concentrated to give the title compound as a yellowoil (0.0667 g). MS (ES): MH⁺ 479.4.

This whole was dissolved in DCM/MeOH (1:1, 2 mL) and treated with 1 MHCl in Et₂O (0.15 mL). After standing for 10 minutes, the solvents wereremoved to give the hydrochloride salt of the title compound (0.053 g)as a pale yellow solid. MS (ES): MH⁺ 479.4.

The following tabulated examples E80-E85 were prepared from theappropriate Boc-protected intermediate as indicated in the table, usingmethods similar to those described for Example 79.

Prepared Example from Boc No. intermediate: Structure E80 D120

E81 D136

E82 D137

E83 D138

E84 D139

E85 D140

Example No. Name Method Comment MH+ E80 N-(3-chloro-4-{[(3S)-3-methyl-1-Similar method to E79 with 469/471 piperazinyl]methyl}phenyl)-6-[(4-column chromatography fluorophenyl)oxy]-N-methyl-3- pyridinecarboxamideE81 N,2′-Dimethyl-N-(4-{[(3S)-3-methyl-1- Similar method to E79 416.3piperazinyl]methyl}phenyl)-2,4′- bipyridine-5-carboxamide E82N-methyl-N-(4-{[(3S)-3-methyl-1 Similar method to E79 with 401.3piperazinyl]methyl}phenyl)-4-(2- reaction time of overnight andpyridinyl)benzamide MDAP purification. Salt formation in MeOH E83N-methyl-N-(4-{[(3S)-3-methyl-1- Similar method to E79 with 402.1piperazinyl]methyl}phenyl)-4-(2- reaction time of overnight andpyrimidinyl)benzamide MDAP purification. Salt formation in MeOH E84N-methyl-N-(4-{[(3S)-3-methyl-1- Similar method to E79 with 390.3piperazinyl]methyl}phenyl)-4-(1H- reaction time of overnight. Saltpyrazol-1-yl)benzamide formation in MeOH E85N-methyl-N-(4-{[(3S)-3-methyl-1- Similar method to E79 with 390.3piperazinyl]methyl}phenyl)-6-(1H- reaction time of overnight. Saltpyrrol-1-yl)-3-pyridinecarboxamide formation in MeOH

Example 86N-Methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-{[4-(trifluoromethyl)phenyl]carbonyl}benzamide(E86)

1,1-Dimethylethyl(2S)-2-methyl-4-[(4-{methyl[(4-{[4-(trifluoromethyl)phenyl]carbonyl}phenyl)carbonyl]amino}phenyl)methyl]-1-piperazinecarboxylate(D123) (0.244 g, 0.41 mmol) was dissolved in 4M HCl in dioxane (5 mL)and the reaction was stirred for 2 h. The solvent was removed in vacuoto give the dihydrochloride salt of the title compound as an off-whitesolid (0.203 g) which was further dried in vacuo. MS (ES): MH⁺ 496.1.

The following tabulated examples E87-E93 were prepared using methodssimilar to those described for Examples E1, E2, E3 or E79.

Example No. Structure Name MH+ E87

5-(4-cyanophenyl)-N-methyl-N-(4- {[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2- pyridinecarboxamide 426.1 E88

6-(4-fluorophenyl)-N-methyl-N-(4- {[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2- pyridinecarboxamide 419.1 E89

N-methyl-N-(4-{[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-4-(6-methyl-3-pyridinyl)benzamide 415.2 E90

N-methyl-N-(4-{[(3S)-3-methyl-1- piperazinyl]methyl}phenyl)-4-(2-pyrazinyl)benzamide 402.1 E91

6-(4-fluorophenyl)-N-methyl-N-(5- {[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-2-pyridinecarboxamide 420.3 E92

6-(3-fluorophenyl)-N-methyl-N-(5- {[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-2-pyridinecarboxamide 420.3 E93

2-[(3-fluorophenyl)oxy]-N-methyl-N-(4- {[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide 434.2

GPR38 FLIPR functional agonist assay protocol 24 hours prior to assay,CHO-K1 cells stably expressing the GPR38 receptor were seeded (10,000cells/well) into poly-D-lysine coated 384-well black-wall, clear-bottommicrotitre plates (Greiner). On the day of assay, media was aspiratedfrom cell plates using a cell washer (leaving 10 ul of media). Cellswere immediately loaded with loading buffer [Tyrodes (Elga water+145 mMNaCl+5 mM KCl+20 mM HEPES+10 mM glucose+1 mM MgCl₂)+1.5 mM CaCl₂+0.714mg/mL Probenicid (predissolved in 1 M NaOH)+0.25 mM brilliant black+2 uMFluo 4 dye], and incubated at 37.5° C. for 1 hour.

Plates were then assayed on a FLuorometric Imaging Plate Reader (FLIPR,Molecular Devices).

Master compound plates were prepared in 100% DMSO. A top concentrationof 3 mM was used (giving 12 μM final concentration in assay) and thiswas serially diluted 1 in 4. 1 ul from the master plate was transferredto a daughter plate, to which 50 μl of compound dilution buffer(Tyrodes+1 mg/mL BSA+1.5 mM CaCl₂) was added. In the FLIPR, 10 ul oftest compound was added to the cells and changes in fluorescencemeasured over a 1 minute timeframe. Maximum change in fluorescence overbaseline was used to determine agonist response and concentrationresponse curves were constructed, using a 4-parameter logistic equation.

In alternative protocols the loading buffer was HBSS {Elga water+137 mMNaCl+5 mM KCl+0.41 mMa KH2PO4(anhyd)+20 mM HEPES+5 mM glucose+0.81 mMMgSO4(anhyd)+1.3 mM CaCl2+4.16 mM NaHCO3}+0.25 mM brilliant black+2 uMFluo 4 dye and the CHO-K1 cells thawed from frozen aliquots and seeded24 hours prior to the assay.

Examples 1 to 86 of the invention have a pEC50≧6.0 in one or more of theFLIPR assays described above.

1. A compound of formula (I):

or a salt thereof, wherein: A is phenyl or a 6-membered heteroaryl ring,optionally substituted with one substituent selected from halogen,C₍₁₋₄₎alkyl and C₍₁₋₄₎alkoxy; R¹ and R² are independently H orC₍₁₋₄₎alkyl; R³ is an optionally substituted phenyl, heteroaryl ring, orheterocyclic ring; B is an optionally substituted phenyl, 6-memberedheteroaryl ring or 6-membered heterocyclic ring connected to the amidecarbon via a carbon atom; Y is a bond, NH, N—C₍₁₋₄₎alkyl, O, C═O, orCH₂; R⁴ is hydrogen, C₍₁₋₄₎alkyl or C₍₁₋₄₎alkoxyalkyl.
 2. The compoundor salt according to claim 1, wherein A is optionally substituted phenylor pyridyl.
 3. The compound or salt according to claim 1, wherein R¹ ishydrogen or methyl.
 4. The compound or salt according to claim 1,wherein R² is hydrogen or methyl.
 5. The compound or salt according toclaim 1, wherein R³ is optionally substituted phenyl, morpholinyl,piperidinyl, oxadiazolyl, pyridyl, pyrimidinyl, imidazolyl, or pyrrolyl.6. The compound or salt according to claim 1, wherein B is optionallysubstituted phenyl, piperidinyl, pyrimidinyl or pyridyl.
 7. The compoundor salt according to claim 1, wherein Y is NH, O, CH₂, C═O or a bond. 8.The compound or salt according to claim 1, wherein R⁴ is hydrogen,methyl, ethyl, methoxyethyl or isopropyl.
 9. The compound or saltaccording to claim 1, wherein: A is optionally substituted phenyl orpyridyl; R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³ isoptionally substituted phenyl, morpholinyl, piperidinyl, oxadiazolyl,pyridyl, pyrimidinyl, imidazolyl, or pyrrolyl; B is optionallysubstituted phenyl, piperidinyl, pyrimidinyl or pyridyl; Y is NH, O,CH₂, C═O or a bond; and R⁴ is hydrogen, methyl, ethyl, methoxyethyl orisopropyl.
 10. The compound or salt according to claim 1, wherein R¹ andR² are other than hydrogen and the piperazine C* carbons have the3R,5S-configuration.
 11. The compound or salt according to claim 9,wherein R¹ and R² are other than hydrogen and the piperazine C* carbonshave the 3R,5S-configuration.
 12. A compound which is:6-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;1-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;6-(4-fluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(4-morpholinyl)-3-pyridinecarboxamide;4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-biphenylcarboxamide;6-(4-fluorophenyl)-2-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;1-[(3-fluorophenyl)carbonyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;1-[(3-fluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;1-(4-chlorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(1-piperidinyl)-3-pyridinecarboxamide;6-(2-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(2,4-difluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3,4-difluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;4-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;6-(3-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(4-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;4-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;N-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-6-(4-fluorophenyl)-N,2-dimethyl-3-pyridinecarboxamide;2-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;N-(4-{[(3R,5S)-3,5-dimethyl-1-piperazinyl]methyl}phenyl)-6-(4-fluorophenyl)-N-methyl-3-pyridinecarboxamide;4-[(2-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;3-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;3-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;6-[(4-fluorophenyl)amino]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;2-(4-fluorophenyl)-N,4-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-5-pyrimidinecarboxamide;2-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-5-pyrimidinecarboxamide;6-(4-fluorophenyl)-N,2-dimethyl-N-(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(4-fluorophenyl)-N-methyl-N-(4-{[(3R)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-biphenylcarboxamide;4′-fluoro-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-biphenylcarboxamide;6-(2-cyanophenyl)-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N-methyl-N-[4-(1-piperazinylmethyl)phenyl]-3-pyridinecarboxamide;6-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-[(2-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N,2-dimethyl-N-[4-(1-piperazinylmethyl)phenyl]-3-pyridinecarboxamide;6-[2-(aminocarbonyl)phenyl]-N,2-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N-methyl-N-(3-methyl-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(2-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-[(3-cyanophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;N-(2-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-fluorophenyl)-N-methyl-3-pyridinecarboxamide;5-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;5-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;N-(2-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide;5-[(3-cyanophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;5-[(4-fluorophenyl)amino]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;1-[(3,4-difluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;1-[(4-fluorophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;N-(3-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-fluorophenyl)-N-methyl-3-pyridinecarboxamide;N-(3-fluoro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide;1-[(3-cyanophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;1-[(4-cyanophenyl)methyl]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-piperidinecarboxamide;6-(3-fluorophenyl)-N-(1-methylethyl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;N-ethyl-6-(3-fluorophenyl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N-[2-(methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(3-methyl-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;6-(4-fluoro-1-piperidinyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;N-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)benzamide;N-ethyl-6-[(4-fluorophenyl)oxy]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(3-pyridinyloxy)-3-pyridinecarboxamide;6-[(3-fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;6-(4,4-difluoro-1-piperidinyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(6-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-pyridinyl)-3-pyridinecarboxamide;5-(4-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;5-(3-cyanophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;N-methyl-5-[3-(methyloxy)phenyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;N-methyl-5-[4-(methyloxy)phenyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;5-(3-fluorophenyl)-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2-pyridinecarboxamide;6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-methyl-5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamide;6-(4-fluorophenyl)-N-methyl-N-(6-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-pyridinyl)-3-pyridinecarboxamide;N,2′-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3,4′-bipyridine-6-carboxamide;6-[(4-fluorophenyl)oxy]-N-[2-(methyloxy)ethyl]-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide;N-(3-chloro-4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-[(4-fluorophenyl)oxy]-N-methyl-3-pyridinecarboxamide;N,2′-dimethyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-2,4′-bipyridine-5-carboxamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(2-pyridinyl)benzamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(2-pyrimidinyl)benzamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-(1H-pyrazol-1-yl)benzamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-6-(1H-pyrrol-1-yl)-3-pyridinecarboxamide;N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-4-{[4-(trifluoromethyl)phenyl]carbonyl}benzamide;or a salt thereof.
 13. A compound, which is6-[(4-fluorophenyl)oxy]-N-methyl-N-(4-methyl-5-{[(3S)-3-methyl-1-piperazinyl]methyl}-2-pyridinyl)-3-pyridinecarboxamideor a salt thereof.
 14. A method of treating gastric stasis in anenterally fed patient, wherein said patient is a human, comprisingadministering to said human a therapeutically effective amount of thecompound or salt according to claim
 1. 15. A pharmaceutical compositioncomprising the compound or salt according to claim 1 and apharmaceutically acceptable carrier.
 16. A process for the preparationof the pharmaceutical composition according to claim 15 comprisingmixing the compound or salt according to claim 1 with a pharmaceuticallyacceptable carrier.
 17. A process for the preparation of the compound orsalt according to claim 1, which process comprises reacting a compoundof formula (II)

wherein R¹, R², A, and R⁴ are as defined in claim 1, and Q is hydrogenor a suitable nitrogen protecting group with a compound of formula:R³—Y—B—C(═O)—L¹ wherein R³, B and Y are as defined in claim 1, and L¹ isa leaving group, using conditions suitable for the formation of an amidebond.
 18. A process for the preparation of the compound or saltaccording to claim 1, which process comprises reacting a compound offormula (VIII)

wherein R¹, R², R⁴, A, B and Q are as defined in claim 1, and L³represents a leaving group with a compound of formula:M¹-Y—R³ wherein R³ and Y are as defined in claim 1, and M¹ representshydrogen or a metal residue, optionally in the presence of a suitablebase and, optionally, a suitable transition metal catalyst, andthereafter optionally carrying out one or more of the followingreactions: a. converting one compound of formula (I) into anothercompound of formula (I); b. removing any protecting group; c. forming asuitable pharmaceutically acceptable salt of the compound of formula(I).